CA3090936A1 - Processes for the preparation of an apoptosis-inducing agent - Google Patents
Processes for the preparation of an apoptosis-inducing agent Download PDFInfo
- Publication number
- CA3090936A1 CA3090936A1 CA3090936A CA3090936A CA3090936A1 CA 3090936 A1 CA3090936 A1 CA 3090936A1 CA 3090936 A CA3090936 A CA 3090936A CA 3090936 A CA3090936 A CA 3090936A CA 3090936 A1 CA3090936 A1 CA 3090936A1
- Authority
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- Prior art keywords
- compound
- formula
- tert
- butyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 113
- 230000008569 process Effects 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 54
- 230000006907 apoptotic process Effects 0.000 title description 3
- 230000001939 inductive effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 223
- 239000003960 organic solvent Substances 0.000 claims abstract description 82
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 26
- -1 C12 alkyl chloroformate Chemical compound 0.000 claims abstract description 25
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 45
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 29
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 26
- 229910052763 palladium Inorganic materials 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 239000003446 ligand Substances 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical group CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 13
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical group CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical group COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 109
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- 239000000203 mixture Substances 0.000 description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 30
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 30
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 30
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 229940125904 compound 1 Drugs 0.000 description 24
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 22
- 229940125782 compound 2 Drugs 0.000 description 22
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 22
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
- 230000003197 catalytic effect Effects 0.000 description 20
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000002002 slurry Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- 229940044613 1-propanol Drugs 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 10
- 239000008096 xylene Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 108091006629 SLC13A2 Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 4
- 239000004201 L-cysteine Substances 0.000 description 4
- 235000013878 L-cysteine Nutrition 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007836 KH2PO4 Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 description 3
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 2
- SPZGXONNVLTQDE-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 SPZGXONNVLTQDE-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 101100028920 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cfp gene Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000012018 catalyst precursor Substances 0.000 description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000010966 qNMR Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- FGXQQTSLFAVOCN-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-6-one Chemical compound O=C1CCCCC11OCCO1 FGXQQTSLFAVOCN-UHFFFAOYSA-N 0.000 description 1
- VUQZKLXKFUBWRP-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridin-5-ol Chemical compound OC1=CN=C2NC=CC2=C1 VUQZKLXKFUBWRP-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- BSXRPCFOXBDGBC-UHFFFAOYSA-N 2-chloro-4,4-dimethylcyclohexene-1-carbaldehyde Chemical compound CC1(C)CCC(C=O)=C(Cl)C1 BSXRPCFOXBDGBC-UHFFFAOYSA-N 0.000 description 1
- ZVJQBBYAVPAFLX-UHFFFAOYSA-N 3,3-dimethylcyclohexan-1-one Chemical compound CC1(C)CCCC(=O)C1 ZVJQBBYAVPAFLX-UHFFFAOYSA-N 0.000 description 1
- XRMZKCQCINEBEI-UHFFFAOYSA-N 4-bromo-2-fluoro-1-iodobenzene Chemical compound FC1=CC(Br)=CC=C1I XRMZKCQCINEBEI-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229910021120 PdC12 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-VQEHIDDOSA-N benzoic acid Chemical compound OC(=O)C1=CC=C[13CH]=C1 WPYMKLBDIGXBTP-VQEHIDDOSA-N 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000000861 blow drying Methods 0.000 description 1
- ZOQCZTRFTARYGJ-UHFFFAOYSA-N chlorooxy(phenyl)borinic acid Chemical compound ClOB(O)C1=CC=CC=C1 ZOQCZTRFTARYGJ-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ABZZOPIABWYXSN-UHFFFAOYSA-N cyclohex-3-en-1-ol Chemical compound OC1CCC=CC1 ABZZOPIABWYXSN-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- ZPGZHSAOCVWZMR-UHFFFAOYSA-N tert-butyl 4-bromo-2-fluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(Br)C=C1F ZPGZHSAOCVWZMR-UHFFFAOYSA-N 0.000 description 1
- 125000004954 trialkylamino group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
- C07C47/457—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Health & Medical Sciences (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Compounds Of Unknown Constitution (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Provided herein is a process for the preparation of a compound of formula (C):
wherein R is Ci to C12 alkyl, which comprises: (a) combining a compound of formula (A):
with R1MgX in an aprotic organic solvent; wherein Rl is Ci to C6 alkyl and X
is Cl, Br or I; and (b) combining a Cl to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C). The process can be used to make compounds that are intermediates in processes for making compounds having antitumor activity, such as the compound of formula Al.
wherein R is Ci to C12 alkyl, which comprises: (a) combining a compound of formula (A):
with R1MgX in an aprotic organic solvent; wherein Rl is Ci to C6 alkyl and X
is Cl, Br or I; and (b) combining a Cl to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C). The process can be used to make compounds that are intermediates in processes for making compounds having antitumor activity, such as the compound of formula Al.
Description
PROCESSES FOR THE PREPARATION OF AN APOPTOSIS-INDUCING AGENT
[0001] This application claims the benefit of United States Provisional Application No.
61/780,621, filed March 13, 2013, and United States Provisional Application No. 61/947,850, filed March 4, 2014, each of which is hereby incorporated by reference herein in its entirety.
FIELD
[0001] This application claims the benefit of United States Provisional Application No.
61/780,621, filed March 13, 2013, and United States Provisional Application No. 61/947,850, filed March 4, 2014, each of which is hereby incorporated by reference herein in its entirety.
FIELD
[0002] Provided herein are processes for the preparation of an apoptosis-inducing agent, and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the processes provided herein.
BACKGROUND
BACKGROUND
[0003] 4-(4- { [2-(4-chloropheny1)-4,4-dim ethyl cyclohex-1-en-l-yl]methyl piperazin -1-y1)-N-( {3 -nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfony1)-2-(1H-pyrro lo [2,3 -b]pyridin-5-yloxy)benzamide (hereafter, "Compound 1") and 4-(4-42-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-ylimethyll pip erazin-l-y1)-N-( {3 -nitro-4-[(1R,4R)-[4-hydroxy-4-methylcyclohexyl]methypamino]phenyl sulfony1)-2-(1H-pyrrolo [2,3 -blpyridin-5 -yloxy)benzamide (hereafter, "Compound 2") are each potent and selective Bc1-2 inhibitors having, inter alia, antitumor activity as apoptosis-inducing agents.
[0004] Compound 1 has the formula:
HI\1) NI \
N N
CI (1)
HI\1) NI \
N N
CI (1)
[0005] Compound 2 has the formula:
) Ni \_ c\N HN-g * Nv1-1C)OH
CI (2)
) Ni \_ c\N HN-g * Nv1-1C)OH
CI (2)
[0006] Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, Compound 2, and other compounds which exhibit potent binding to a Bc1-2 family protein, and pharmaceutically acceptable salts thereof U.S. Patent Publication Nos.
2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds.
U.S. Patent Publication No. 2012/0129853 describes methods for the treatment of systemic lupus erythematosus, lupus nephritis or Sjogren's Syndrome comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1.
SUMMARY
2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds.
U.S. Patent Publication No. 2012/0129853 describes methods for the treatment of systemic lupus erythematosus, lupus nephritis or Sjogren's Syndrome comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1.
SUMMARY
[0007] Provided herein are processes for the preparation of compounds of formula Al:
HNr'l Ni \_ N N 0 NH \¨R2 CI (Al), OH
wherein R2 is selected from -( __________ / and OC
=
HNr'l Ni \_ N N 0 NH \¨R2 CI (Al), OH
wherein R2 is selected from -( __________ / and OC
=
[0008] Also provided herein are compounds of the formulae:
) Ni \¨
N\ CO2R
Br and CI
wherein R is C1 to C12 alkyl; and processes for their preparation.
DETAILED DESCRIPTION
) Ni \¨
N\ CO2R
Br and CI
wherein R is C1 to C12 alkyl; and processes for their preparation.
DETAILED DESCRIPTION
[0009] Provided herein is a process for the preparation of compounds of formula Al:
N)/
\¨
/ HN- * NH
N N \-R2 CI (Al), \c)=
wherein R2 is selected from \ / and which comprises:
(a) combining a compound of formula (K):
o CI (K) wherein R is Ci to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
*
(N) CI (L); and (b") combining the compound of formula (L) with 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), an organic solvent, and either a compound of formula (N), to provide a compound of formula +CO
(Al) wherein R2 is o 0 (N) or a compound of formula (P), to provide a compound of formula (Al) wherein R2 is "i 00e. H
H2N- = 6 (P);
thereby providing a compound of formula (Al).
-1-( \O
N)/
\¨
/ HN- * NH
N N \-R2 CI (Al), \c)=
wherein R2 is selected from \ / and which comprises:
(a) combining a compound of formula (K):
o CI (K) wherein R is Ci to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
*
(N) CI (L); and (b") combining the compound of formula (L) with 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), an organic solvent, and either a compound of formula (N), to provide a compound of formula +CO
(Al) wherein R2 is o 0 (N) or a compound of formula (P), to provide a compound of formula (Al) wherein R2 is "i 00e. H
H2N- = 6 (P);
thereby providing a compound of formula (Al).
-1-( \O
[0010] In one embodiment, R- is "11 00e H
[0011] In another embodiment, R2 is
[0012] In some embodiments, R is Ci to C6 alkyl. In some embodiments, R is Ci to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
[0013] In one embodiment, the process provided herein further comprises:
(c") combining a compound of formula (M):
CI
NH2 (M) with a tertiary amine base, an organic solvent, and either (tetrahydro-2H-pyran-4-yl)methanamine or a salt thereof, to provide the compound of formula (N), or (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol or a salt thereof, to provide the compound of formula (P).
(c") combining a compound of formula (M):
CI
NH2 (M) with a tertiary amine base, an organic solvent, and either (tetrahydro-2H-pyran-4-yl)methanamine or a salt thereof, to provide the compound of formula (N), or (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol or a salt thereof, to provide the compound of formula (P).
[0014] In one embodiment, the (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol salt of step (c") is the p-toluenesulfonic acid salt.
[0015] In another embodiment, the process provided herein further comprises:
(d) combining a compound of formula (D):
Br (D) wherein R is Ci to C12 alkyl, with a compound of formula (I):
rN
1.N.J 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).
(d) combining a compound of formula (D):
Br (D) wherein R is Ci to C12 alkyl, with a compound of formula (I):
rN
1.N.J 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).
[0016] In some embodiments, the phosphine ligand is a compound of formula (J):
NMe2 (j).
NMe2 (j).
[0017] In other embodiments, the phosphine ligand is selected from:
>LYJ<
Br *
Fe + Fe Pd c1=P'P)c CI
BF4 I \
>LYJ<
Br *
Fe + Fe Pd c1=P'P)c CI
BF4 I \
[0018] In another embodiment, the process provided herein further comprises:
(e) combining a compound of formula (B) with a compound of formula (C):
HO
N
H (B) Br (C) wherein R is C1 to C12 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
(e) combining a compound of formula (B) with a compound of formula (C):
HO
N
H (B) Br (C) wherein R is C1 to C12 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
[0019] In another embodiment, the process provided herein further comprises:
(f) combining a compound of formula (A):
F
Br (A) with RiMgX in an aprotic organic solvent;
wherein Rl is C1 to C6 alkyl; and X is CI, Br or I; and (g) combining a C1 to C12 alkyl chlorofornate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (1), to provide the compound of formula (C).
(f) combining a compound of formula (A):
F
Br (A) with RiMgX in an aprotic organic solvent;
wherein Rl is C1 to C6 alkyl; and X is CI, Br or I; and (g) combining a C1 to C12 alkyl chlorofornate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (1), to provide the compound of formula (C).
[0020] In another embodiment, the process provided herein further comprises:
(h) combining a compound of formula (E):
OjCi< (E) with DMF and POC13 to provide a compound of formula (F):
CI (F);
combining the compound of formula (F) with a source of palladium and 4-ehlorophenylboronic acid in an organic solvent to provide a compound of formula (G):
CI (G);
(1) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H):
Boc N"
Cl (H); and (k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (1).
(h) combining a compound of formula (E):
OjCi< (E) with DMF and POC13 to provide a compound of formula (F):
CI (F);
combining the compound of formula (F) with a source of palladium and 4-ehlorophenylboronic acid in an organic solvent to provide a compound of formula (G):
CI (G);
(1) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H):
Boc N"
Cl (H); and (k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (1).
[0021] In one embodiment, the process comprises step (a), step (b"), step (e") and step (d).
In one embodiment, the process comprises step (a), step (b"), step (c"), step (d) and step (e). In one embodiment, the process comprises step (a), step (b"), step (c"), step (d), step (e), step (0 and step (g). In another embodiment the process comprises step (a), step (b"), step (c"), step (d), step (e), step (0, step (g), step (h), step (i), step (j) and step (k).
In one embodiment, the process comprises step (a), step (b"), step (c"), step (d) and step (e). In one embodiment, the process comprises step (a), step (b"), step (c"), step (d), step (e), step (0 and step (g). In another embodiment the process comprises step (a), step (b"), step (c"), step (d), step (e), step (0, step (g), step (h), step (i), step (j) and step (k).
[0022] In one embodiment, the process comprises steps (a), (b") and (d). In another embodiment, the process comprises steps (a), (b"), (d) and (e). In another embodiment, the process comprises steps (a), (b"), (d), (h), (i), (j) and (k). In another embodiment, the process comprises steps (a), (b"), (c"), (d), (h), (i), (j) and (k). In another embodiment, the process comprises steps (a), (b"), (d), (0, (g), (h), (i), (j) and (k). In another embodiment, the process comprises steps (a), (b"), (d), (e), (0, (g), (h), (i), (j) and (k).
[0023] Also provided herein is a process for the preparation of Compound 1 of the formula:
HN
Ni \¨
= HN- ,. NH
N N
o 0 CO
CI
which comprises:
(a) combining a compound of formula (K):
o CI (K) wherein R is C1 to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
N
(N) CI (L);
(b) combining the compound of formula (L) with a compound of formula (N):
9=
O
0 (N); and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of formula (1).
HN
Ni \¨
= HN- ,. NH
N N
o 0 CO
CI
which comprises:
(a) combining a compound of formula (K):
o CI (K) wherein R is C1 to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
N
(N) CI (L);
(b) combining the compound of formula (L) with a compound of formula (N):
9=
O
0 (N); and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of formula (1).
[0024] In some embodiments, R is Ci to C6 alkyl. In some embodiments, R is C1 to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
[0025] In one embodiment, the process for the preparation of Compound 1 further comprises:
(c) combining a compound of formula (M):
ci o=s, NH2 (M) with (tetrahydro-2H-pyran-4-yl)methanamine, a tertiary amine base, and an organic solvent to provide the compound of formula (N).
(c) combining a compound of formula (M):
ci o=s, NH2 (M) with (tetrahydro-2H-pyran-4-yl)methanamine, a tertiary amine base, and an organic solvent to provide the compound of formula (N).
[0026] In another embodiment, the process for the preparation of Compound 1 further comprises:
(d) combining a compound of formula (D):
Br (D) wherein R is C1 to C12 alkyl, with a compound of formula (I):
L.NJ 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).
(d) combining a compound of formula (D):
Br (D) wherein R is C1 to C12 alkyl, with a compound of formula (I):
L.NJ 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).
[0027] In some embodiments, the phosphine ligand is a compound of formula (J):
L
NMe2 (j).
L
NMe2 (j).
[0028] In other embodiments, the phosphine ligand is selected from:
_dper,pdti_ _____________________________________________________________________ P\ci ,HZ
Fe 13r'- + \
%=7-.)c- µ Fe Pd µ=_/P
CI
_dper,pdti_ _____________________________________________________________________ P\ci ,HZ
Fe 13r'- + \
%=7-.)c- µ Fe Pd µ=_/P
CI
[0029] In another embodiment, the process for the preparation of Compound 1 further comprises:
(e) combining a compound of formula (B) with a compound of formula (C):
HO is F
H (B) Br (C) wherein R is C1 to C12 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
(e) combining a compound of formula (B) with a compound of formula (C):
HO is F
H (B) Br (C) wherein R is C1 to C12 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
[0030] In another embodiment, the process for the preparation of Compound 1 further comprises:
(I) combining a compound of formula (A):
Br (A) with RiMgX in an aprotic organic solvent;
wherein Rl is C1 to C6 alkyl; and X is Cl, Br or I; and (g) combining a Ci to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (0, to provide the compound of formula (C).
(I) combining a compound of formula (A):
Br (A) with RiMgX in an aprotic organic solvent;
wherein Rl is C1 to C6 alkyl; and X is Cl, Br or I; and (g) combining a Ci to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (0, to provide the compound of formula (C).
[0031] In another embodiment, the process for the preparation of Compound 1 further comprises:
(h) combining a compound of formula (E):
O (E) with DMF and POC13 to provide a compound of formula (F):
CI SI (F);
(I) combining the compound of formula (F) with a source of palladium and chlorophenylboronic acid in an organic solvent to provide a compound of formula (G):
CI (G);
(1) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H):
Bo c CI (H); and (k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (I).
(h) combining a compound of formula (E):
O (E) with DMF and POC13 to provide a compound of formula (F):
CI SI (F);
(I) combining the compound of formula (F) with a source of palladium and chlorophenylboronic acid in an organic solvent to provide a compound of formula (G):
CI (G);
(1) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H):
Bo c CI (H); and (k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (I).
[0032] In one embodiment, the process for the preparation of Compound 1 comprises steps (a) through (d). In one embodiment, the process for the preparation of Compound 1 comprises steps (a) through (e). In another embodiment, the process for the preparation of Compound 1 comprises steps (a) through (g). In another embodiment, the process for the preparation of Compound 1 comprises steps (a) through (k).
[0033] In one embodiment, the process for the preparation of Compound 1 comprises steps (a), (b) and (d). In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d) and (e). In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (c), (d), (h), (i), (j) and (k).
In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d), (0, (g), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d), (e), (0, (g), (h), (i), (j) and (k).
[0034[ Also provided herein is a process for the preparation of Compound 2 of the formula:
HN"..1 Ni o c\N = HN-g =Nv1-1.,,,0e0H
Cl (2) which comprises:
(a) combining a compound of formula (K):
CI (K) wherein R is C1 to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
0õ
'1\1 (N) CI (L);
(b') combining the compound of formula (L) with a compound of formula (P):
H2N- 411 NH [\,0H
0 (P); and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of formula (2).
[0035] In some embodiments, R is C1 to C6 alkyl. In some embodiments, R is C1 to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and nco-butyl. In some embodiments, R is tut-butyl.
[0036] In one embodiment, the process for the preparation of Compound 2 further comprises:
(c') combining a compound of formula (M):
CI
Oc1ES
NH2 (M) with (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol or a salt thereof, a tertiary amine base, and an organic solvent to provide the compound of formula (P).
[0037] In one embodiment, the (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol salt of step (c') is the p-toluenesulfonic acid salt.
[0038] In some embodiments, the method for the preparation of Compound 2 further comprises step (d) as described above for the preparation of Compound 1.
[0039] In some embodiments, the method for the preparation of Compound 2 further comprises step (e) as described above for the preparation of Compound 1.
[0040] In some embodiments, the method for the preparation of Compound 2 further comprises step (0 and step (g) as described above for the preparation of Compound 1.
[0041] In some embodiments, the method for the preparation of Compound 2 further comprises step (h), step (i), step (j) and step (k) as described above for the preparation of Compound 1.
[0042] In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c') and step (d). In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d) and step (e). In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d), step (e), step (f) and step (g). In another embodiment the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d), step (e), step (0, step (g), step (h), step (i), step (j) and step (k).
[0043] In one embodiment, the process for the preparation of Compound 2 comprises steps (a), (b') and (d). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d) and (e). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (c'), (d), (h), (i), (j) and (k).
In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (0, (g), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (e), (0, (g), (h), (i), (j) and (k).
[0044] In some embodiments, in step (a) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (a) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step (a) the tert-butoxide salt is potassium tert-butoxide.
[0045] In some embodiments, in step (a) the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (a) the aprotic organic solvent is 2-methyltetrahydrofuran.
[0046] In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is dichloromethane.
[0047] In some embodiments, in step (c), step (c') and/or step (c") the tertiary amine base is N,N-diisopropylethylamine.
[0048] In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is acetonitrile.
[0049] In some embodiments, in step (d) the compound of formula (I) is first combined with a base prior to the combining of step (d). In some embodiments, the base is an inorganic base.
In some embodiments, the base is an organic base. In some embodiments, the base is selected from the group consisting of K3PO4, Na3PO4, NaOH, KOH, K2CO3 or Na2CO3. In some embodiments, the base is K31304. In some embodiments, in step (d) the compound of formula (I) is first combined with a base in one or more solvents prior to the combining of step (d).
[0050] In some embodiments, in step (d) the source of palladium is Pd2dba3 or [(cinnamyl)PdC1]2. In some embodiments, in step (d) the source of palladium is Pd2dba3.
[0051] In some embodiments, in step (d) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0052] In some embodiments, in step (d) the tert-butoxide salt is anhydrous. In some embodiments, in step (d) the tert-butoxide salt is anhydrous sodium tert-butoxide.
[0053] In some embodiments, in step (d) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (d) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof In some embodiments, in step (d) the aprotic organic solvent is a mixture of THF and toluene.
[0054] In some embodiments, step (d) further comprises the following steps:
(1) combining the tert-butoxide salt with the compound of formula (I) in an aprotic organic solvent;
(2) combining the source of palladium, the compound of formula (J), and the compound of formula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).
[0055] In some embodiments, in step (d) the mixture resulting from step (2) is filtered prior to step (3).
[0056] In some embodiments, step (d) is carried out under an atmosphere of nitrogen or argon.
[0057] In some embodiments, in step (d) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd2dba3 and the catalytic amount of Pd2dba3 is from about 0.5 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of Pd2dba3 is about 0.75 mole percent.
[0058] In some embodiments, in step (d) a catalytic amount of the compound of formula (J) is used relative to the amount of compound (I). In some embodiments, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 2 mole percent.
In one embodiment, the catalytic amount of the compound of formula (J) is about 1 mole percent or about 2 mole percent.
[0059] In some embodiments, in step (e) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (e) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step (e) the tert-butoxide salt is potassium tert-butoxide.
[0060] In some embodiments, in step (e) the organic solvent is selected from the group consisting of pentane, hexane, hcptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1 -butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (e) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (e) the organic solvent is DMF.
[0061] In some embodiments, in step (f), RI is C1 to C4 alkyl. In some embodiments, Rl is isopropyl.
[0062] In some embodiments, in step (f), R is methyl and the Ci to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, R is ethyl and the C1 to C12 alkyl chloroformate is ethyl chloroformate. In some embodiments, R is tert-butyl and the di-(Ci to alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0063] In some embodiments, in step (f) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxanc, nitromethanc, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (f) the aprotic organic solvent is THF.
[0064] In some embodiments, in step (i) the source of palladium is Pd(OAc)2.
[0065] In some embodiments, in step (i) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is acetonitrile.
[0066[ In some embodiments, step (i) comprises combining tetrabutylammonium bromide with the compound of formula (F), a source of palladium and 4-chlorophenylboronic acid in the organic solvent.
[0067] In some embodiments, in step (j) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (j) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (j), the organic solvent is a mixture of THF and toluene.
In some embodiments, the mixture of THF and toluene is about 1:1 by volume.
[0068] In some embodiments, step (j) further comprises producing the compound of formula (H) as a crystalline solid. In some embodiments, step (j) further comprises:
(1) adding an aqueous solution to the mixture of step (j) to produce an aqueous and an organic phase;
(2) separating the organic phase from the mixture of step (1);
(3) concentrating the organic phase; and (4) adding an organic solvent to the mixture of step (3) to produce the compound of formula (H) as a crystalline solid.
[0069] In some embodiments of step (4) of step (j), the organic solvent is acetonitrile. In some embodiments of step (4) of step (j), the organic solvent is acetonitrile and the mixture is heated to about 80 'C.
[0070] In some embodiments, step (4) of step (j) further comprises cooling the mixture to about 10 C to about -10 C. In some embodiments, step (4) of step (j) further comprises cooling the mixture to about -10 C, and isolating the compound of formula (H) as a crystalline solid by filtering the mixture.
[0071] In some embodiments, the combining of step (k) is in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1 -propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the organic solvent is isopropanol.
[0072] In some embodiments, step (k) further comprises producing the compound of formula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in an organic solvent, and step (k) further comprises isolating the compound of formula (I) as a crystalline solid by filtering the mixture.
[0073] In some embodiments, the combining of step (k) is in an organic solvent, and step (k) further comprises cooling the mixture to about 10 C to about -10 C to produce the compound of formula (I) as a crystalline solid.
[0074] In some embodiments, the combining of step (k) is in isopropanol, and step (k) further comprises cooling the mixture to about 10 C to about -10 C to produce the compound of formula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in isopropanol, and step (k) further comprises cooling the mixture to about -5 C
to produce the compound of formula (I) as a crystalline solid, and isolating the compound of formula (I) as a crystalline solid by filtering the mixture.
[0075] Also provided herein is a process of preparing a compound of formula (C):
F
Br (C) wherein R is C1 to C12 alkyl, which comprises (a) combining a compound of formula (A):
is F
Br (A) with RiMgX in an aprotic organic solvent; wherein Rl is CI to C6 alkyl; and X
is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
[0076] In some embodiments, R is C1 to C6 alkyl. In some embodiments, R is C1 to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
[0077] In some embodiments, RI is C1 to C4 alkyl. In some embodiments, Rl is isopropyl.
[0078] In some embodiments of the process of preparing a compound of formula (C), the organic solvent of step (a) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments the organic solvent of step (a) is THF.
[0079] In one embodiment, R is C1 to C6 alkyl.
[0080] In one embodiment, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.
[0081] In one embodiment, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl; and 121 is isopropyl.
[0082] In one embodiment, R is tert-butyl and RI- is isopropyl.
[0083] In some embodiments of the process of preparing a compound of formula (C), in step (b), R is methyl and the C1 to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, R is ethyl and the C1 to C12 alkyl chloroformate is ethyl chloroformate. In some embodiments, R is tert-butyl and the di-(Ci to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0084] Also provided herein is a process for the preparation of a compound of formula (D):
Br (D) wherein R is C1 to C12 alkyl, which comprises:
(x) combining a compound of formula (B):
HOrrs N
H (B);
with a compound of formula (C):
F
Br (C) and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
[0085] In one embodiment, R is tert-butyl.
[0086] In some embodiments, the process of preparing the compound of formula (D) further comprises steps (x') and (x"):
(x') combining a compound of formula (A):
F
Br (A) with RiMgX in an aprotic organic solvent; wherein R' is C1 to C6 alkyl; and X
is Cl, Br or I;
(x") combining a C1 to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (x'), to provide the compound of formula (C).
[0087] In some embodiments, in step (x) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0088] In some embodiments, the organic solvent of step (x) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the organic solvent of step (x) is DMF.
[0089] In some embodiments, in step (x'), RI- is a C1 to C4 alkyl. In some embodiments, RI is isopropyl.
[0090] In some embodiments, in step (x"), the C1 to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, the C1 to C12 alkyl chloroformate is ethyl chloroformate.
In some embodiments, the di-(Ci to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0091] In some embodiments, in step (x') the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (x') the aprotic organic solvent is THF.
[0092] Also provided herein is a compound of the formula (3):
HNIr ) N
\N =CO2tBu CI
[0093] In one embodiment, the compound of the formula (3) is prepared by the following steps:
(y) combining a compound of formula (B):
HO
H (B);
with a compound of formula (C):
F
Br (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D):
Br (D), wherein R is tert-butyl; and (z) combining the compound of formula (D), wherein R is tert-butyl;
with a compound of formula (I):
(N) 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent.
[0094] In one embodiment, the phosphine ligand of step (z) is a compound of formula (J):
>LIDJ
NMe2 [0095] In other embodiments, the phosphine ligand is selected from:
>W<
)1=., ___________________________________ Br +
¨\04-P'P
\
/.+C)9 Fe Br + Fe Pd BF4 7c I\
[0096] In one embodiment, in step (z) the source of palladium is Pd2dba3.
[0097] In some embodiments, in step (z) the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THE, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the aprotic organic solvent is is a mixture of THF and toluene.
[0098] In some embodiments, in step (z), the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0099] In some embodiments, in step (z) the tert-butoxide salt is anhydrous sodium tert-butoxide or anhydrous potassium tert-butoxide.
[00100] In some embodiments, step (z) further comprises the following steps:
(1) combining the tert-butoxide salt with the compound of formula (I) in an aprotic organic solvent;
(2) combining the source of palladium, the compound of formula (J), and the compound of formula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).
[00101] In some embodiments, in step (z) the mixture resulting from step (2) is filtered prior to step (3).
[00102] In some embodiments, step (z) is carried out under an atmosphere of nitrogen or argon.
[00103] In some embodiments, in step (z) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd2dba3 and the catalytic amount of Pd2dba3 is from about 0.5 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of Pd2dba3 is about 0.75 mole percent.
[00104] In some embodiments, when the phosphine ligand of step (z) is a compound for formula (J), a catalytic amount of the compound of formula (J) is used relative to the amount of compound (1). In some embodiments, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is about 1 mole percent or about 2 mole percent.
[00105] In another embodiment, provided herein are compounds of the formulae:
HNrsµk N/
\_ CO2tBu 0 =
N/--\N CO2tBu N
Br and CI
[00106] In some embodiments, the processes described herein are improved methods for commercial chemical manufacturing of Compound 1 or Compound 2. Without being bound to a particular theory or mechanism of action, the processes described herein significantly improve the overall efficiency and product yield of Compound 1 or Compound 2. Previous processes (e.g., U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and International Patent Publication Nos. WO 2011/15096 and WO 2012/071336) were found to lack feasibility for production of Compound 1 on a commercial scale. Thus, the processes provided herein represent improved methods for the synthesis of compounds in quantities required for clinical and/or commercial development. Improvements relative to these previous processes include, but are not limited to, overall yield of Compound 1 or Compound 2, overall process efficiency and economics, mild reaction conditions, practical isolation/purification procedures, and viability for commercialization.
[00107] The improved process provided herein involves a selective nucleophilic aromatic substitution reaction ("SnAr reaction") of compounds (B) and (C), which can be carried out under milder conditions with a shorter reaction time when compared to previously described processes as found, for example, in U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and International Patent Publication Nos. WO 2011/15096 and WO
2012/071336. Without being limited by theory, the improved SnAr reaction of compound (B) and (C) does not generate regioisomeric side products which necessitate further purification to remove the side products, as was the case in previously described processes.
The SnAr reaction in the previous process also requires a longer reaction time and harsh reaction conditions which result in a low overall yield relative to the processes described herein.
Furthermore, the previous processes also require tedious purification of the intermediates which is impracticable on a large, commercial scale process. The processes described herein are more convergent than prior processes, resulting in a highly efficient cross-coupling reaction of compound (D) and the free base of compound (I) in high yield. In some embodiments, the processes described herein utilize crystalline solid intermediates (H) and (I), which allow efficient purification by crystallization to remove impurities ¨ advantages not available in previously described processes.
[00108] The following schemes illustrate one or more embodiments of the process provided herein. In some embodiments, the compound of formula (D) is prepared from compound (B) and compound (C) as shown in Scheme 1 below. The compound of formula (B) may be prepared by techniques known in the art, e.g., as shown in WO 2000/047212 and I Am. Chem.
Soc., 1959, 81: 743-747. The compound of formula (C) may be prepared by techniques known in the art, e.g., as shown in WO 2006/059801 and Tetrahedron Letters, 2008, 49(12), 2034-2037;
or as shown in Scheme 2.
Scheme 1 F
HOrn = CO2R
N Br =
N N
KOtBu / DMF Br [00109] The compound of formula (C) of Scheme 1 may prepared from commercially available compound (A) as shown in Scheme 2 below, wherein "RiMgX" represents a Grignard reagent wherein Rl is an alkyl group, and X is Cl, Br or I. The electrophilic acetylating reagent of Scheme 2 can be, but is not limited to, methyl or ethyl chloroformate or BOC20.
Scheme 2 1. RiMgBr 002R
F 2. Electrophilic acylating reagent F
Br Br A
[00110] An exemplary reaction according to Scheme 2 is shown below.
1. iPrMgBr CO2tBu ioF 2. Boc20 F
Br Br [00111] In another embodiment, the compound of formula (I) is prepared from compound (E) as shown in Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. 3,813,443 and Proceedings of the Chemical Society, London, 1907, 22, 302.
Scheme 3 9 Boc Boc OH
9 gi B.OH j THF,N) CNJ
DMF, POCI3 N tolunene HCI, IPA
0 CI 4111"
Pd(OAc)2 CI
MeCN
CI
CI
[00112] In another embodiment, the compound of formula (N) is prepared from compound (M) as shown in Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 and J. Am. Chem.
Soc., 1950, 72, 1215-1218.
Scheme 4 H2Ni ( -3 NO2 NO2 H
cl el CI MeCN, DIEA Q
[00113] In another embodiment, the compound of formula (P) is prepared from compound (M) as shown in Scheme 4' below.
Scheme 4' CH3MgBr Toluene ir I-110 HCI
-b. HC[1 i:;,1 1 Toluene, 80 C
H2N/--\N,., I' õ
Alb.
illi 0 0 _20 _ 30 C 0 0 \__/ \__/ 0 I
ON
el.,PCy3 lc HO
[I HO,,.
0 PF6 ...--1) RaNi, wet! H2 Crabtree's cat. THF
________________________________________ p¨
DCM, 30 C 2) MeCN / pTSA
02N pTSA H2N
dr > 99%
HO,,, 1:1 (3%
0-.2S% NO2 0 CI MeCN, DIEA
+
_________________________________________ - H2N¨S 4. N OH
H
8 .
pTSA H2N m [00114] In another embodiment, the compound of formula (1) is prepared from compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in WO 2009/117626 and Organometallies, 2008, 27(21), 5605-5611.
Scheme 5 co2R
. n N.- N CO2R CO2H
H
Br D > 0 orn LiDk 0 oT
N' N
+ z 01 J N N
H N H
NMe2 (N) baseND L
H -,-(1\1 ,1 2HCI K
Pd2dba3 -0tBu (1 CI CI
CI I
CO2H 9 =
0=S
() 0 NH
EDAC, DMAP
(N) ,H2,12 CI L (1) CI
[00115] In another embodiment, the compound of formula (2) is prepared from compound (L) and compound (P) as shown in Scheme 6 below, wherein the preparation of compound (P) is as shown in Scheme 4' and the preparation of compound (L) is as shown in Scheme 5.
Scheme 6 H
op 0 NH
-s NO2 C
d EDAC, DMAPOOH
NH
CH2Cl2 CI L (2) CI
[00116] In some embodiments, the preparation of the compound of formula (K) from compound (D) and compound (I) is air and/or moisture sensitive, and is therefore performed under an inert atmosphere, e.g., using nitrogen or argon gas.
[00117] Without being bound to a particular theory, the use of compound (D) as an intermediate in the preparation of the compound of formula (1) and the compound of formula (2) as shown above in Schemes 1 to 6 is an improvement over previously described processes for the preparation of the compound of formula (1) and the compound of formula (2). In some embodiments, the improvements include higher product yields, shorter reaction times. In some embodiments, the improvements are provided when R is tert-butyl in compound (D).
[00118] Schemes 1 to 6 are non-limiting examples of the process provided herein. Solvents and/or reagents are known compounds and may be interchanged according to the knowledge of those skilled in the art.
[00119] Abbreviations used in Schemes 1 to 6 are as follows:
Ac acetyl BOC tert-butoxycarbonyl dba dibenzylidineacetone DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide EDAC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 IPA isopropanol iPr isopropyl Me methyl n-Bu n-butyl tBu tert-butyl THF tetrahydrofuran [00120] Unless indicated otherwise, the temperatures at which a reaction of Schemes 1 to 6 is conducted is not critical. In certain embodiments, when a temperature is indicated in a reaction, the temperature may be varied from about plus or minus 0.1 C, 0.5 C, 1 C, 5 C, or 10 C.
Depending upon which solvent is employed in a particular reaction, the optimum temperature may vary. In some embodiments, reactions are conducted in the presence of vigorous agitation sufficient to maintain an essentially uniformly dispersed mixture of the reactants.
[00121] In conducting a reaction provided herein, neither the rate, nor the order, of addition of the reactants is critical unless otherwise indicated. Unless otherwise indicated, reactions are conducted at ambient atmospheric pressure. Unless otherwise indicated, the exact amount of reactants is not critical. In some embodiments, the amount of a reactant may be varied by about mole percent or about 10% by weight.
[00122] Unless otherwise indicated, the organic solvents used in the processes provided herein may be selected from those commercially available or otherwise known to those skilled in the art. Appropriate solvents for a given reaction are within the knowledge of the skilled person and include mixtures of solvents. Examples of organic solvents provided herein for use include but are not limited to: pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), hexamethylphosphoramide (HMPA), N-methyl-2-pyrrolidinone (NMP), nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof.
[00123] In some embodiments, an organic solvent used in the processes provided herein is an aprotic organic solvent. As provided herein, an aprotic solvent is a solvent that does not contain an acidic hydrogen atom or a hydrogen atom that is capable of hydrogen bonding (e.g., is not bound to an oxygen or a nitrogen atom). The aprotic organic solvent may be selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the aprotic organic solvent is THF. In some embodiments, the aprotic organic solvent is DMF. In some embodiments, the aprotic organic solvent is acetonitrile.
[00124] As provided herein, a "tertiary amine base" refers to an amine that is substituted with three alkyl groups, e.g., triethylamine or N,N-diisopropyl ethyl amine.
[00125] As provided herein, a "catalytic amount" refers to less than one molar equivalent of a reagent or reactant in a given reaction, as determined relative to another reagent or reactant in the reaction mixture. In some embodiments, a catalytic amount is described as a mole percent relative to another reagent or reactant in the reaction mixture.
[00126] As provided herein, a "source of palladium" refers to a source of palladium in a stable oxidation state, i.e., Pd(0), Pd(I), Pd(II) and/or Pd(IV). The palladium may be free metal, such as in a powder form, or may be bound to one or more ligands, e.g., PdC12, Pd2dba3, PdC12(PPh3)2, Pd(PPh3)4, Pd(OAc)2 or [(cinnamyl)PdC1]2.
[00127] As provided herein, a "phosphine ligand" refers to a compound of formula PR'1, wherein each R' is independently selected from CI to C6 alkyl or phenyl, wherein the aryl group is optionally substituted by C1 to C6 alkyl, phenyl, trialkylamino, alkoxy or halo.
[00128] As provided herein, unless otherwise defined, the term "about" means that the value or amount to which it refers can vary by 5%, 2%, or 1%.
[00129] The products obtained by any of the processes provided herein may be recovered by conventional means, such as evaporation or extraction, and may be purified by standard procedures, such as distillation, recrystallization or chromatography EXAMPLES
[00130] Compounds of the following examples are shown in Schemes 1 to 6 above and were named using Chemdraw0 Ultra software. In addition to the abbreviations described above with respect to the schemes provided herein, the following abbreviations are used in the Examples:
[00131] "HPLC" = high pressure liquid chromatography; "IP" = in process; "ML"
= mother liquor; "NLT" = no less than; "NMT" = no more than; "RB" = round bottom; "RT"
= room temperature; "sm" = starting material; "DCM" = dichloromethane.
[00132] Unless indicated otherwise, compounds were characterized by HPLC and analysis and used in later reactions with or without purification. 1H NMR
analysis was perfoimed at 400 MHz unless otherwise indicated. Unless specified otherwise, product yield/purity was determined by weight, qNMR, and/or HPLC analysis.
Example 1: Synthesis of tert-butyl 4-bromo-241uorobenzoate (Compound (C)) [00133] To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro 1 -iodobenzene, "Compound (A)" (5 g, 1.0 eq) and THF (25 m1).
The solution was cooled to -5 C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0 C. The mixture was stirred at 0 C for 1 h.
Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10 % citric acid (10 ml), and then diluted with 25 % NaC1 (10 m1). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3 x m1). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency = 67%, potency adjusted yield = 88%) was taken to the next step without further purification. Ili NMR (DMSO-d6): 6 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H),7.74 (t, J= 8.2 Hz, 1H).
Example 2: Synthesis of tert-butyl 2-41H-pyrrolo[2,3-b]pyridin-5-y0oxy)-4-bromobenzoate (Compound (D)) [00134] To a 3 L three-neck Morton flask were charged 1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20 C for 15 min. The resulting solution was cooled to about zero to 5 'C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10 C, and rinsed with DMF (30 mL). The reaction mixture was stirred at 10 'V for 1 hour (an off-white slurry) and adjusted the internal temperature to - 45 C over 30 min. The reaction mixture was stirred at 45-50 C for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion %
by HPLC).
The solution was cooled to - 20 C. The solution was stirred at 20 C
overnight.
[00135] Water (1200 mL) was added slowly to the reaction mixture at <30 C
over lhour (slightly exothermic). The product slurry was adjusted to - 20 C, and mixed for NLT 2 hours.
The crude product was collected by filtration, and washed with water (400 naL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50 C overnight to give the crude product (236.7g).
[00136] Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted:
200.7 g) was charged back to a 3L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over lhr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78 C). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to - -10 C at a rate of approximate 10 C/hour), and mixed for 2hr. The product was collected by filtration, and rinsed with heptane (200 m1).
[00137] The solid was dried under vacuum at - 50 C overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191 C
(uncorrected).
1H NMR (DMSO-d6): 6 1.40 (s, 9H), 6.41 (dd, J= 3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J= 8.3, 1.8 Hz, 1H), 7.51 (t, J= 3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
Example 3: Synthesis of 2-ehloro-4,4-dimethyleyelohexanecarbaldehyde (Compound (F)) [00138] To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456mo1) and (80 mL). The solution was cooled down <-5 C, and P0C13 (64.7 g, 0.422 mol) added slowly over 20 min (ci) <20 C (exothermic), rinsed with CH2C12 (6 mL). The slightly brown solution was adjusted to 20 C over 30 min, and mixed at 20 C for 1 hour. The solution was cooled back to < 5 C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ¨0.292 mol) was added, and rinsed with in CH2C12 (10 mL) (slightly exothermic) at <20 'V The solution was heated to refluxing temperature, and mixed overnight (21 hours.).
[00139] To a 1000 mL three neck RB flask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12%
brine, and 130 mL
of CH2C12. The mixture was stirred and cooled down to <5 C. The above reaction mixture (clear and brown) was transferred, quenched into it slowly while maintaining the internal temperature <10 C. The reaction vessel was rinsed with CH2C12 (10 mL). The quenched reaction mixture was stirred at <10 C for 15 min. and allowed to rise to 20 C. The mixture was stirred 20 'V for 15 min and allowed to settle for 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extracted with CH2C12 (50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K3PO4 aq. solution (40 g). The organic was dried over MgSO4, filtered and rinsed with CH2C12 (30 ml). The filtrate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency=90.9wt% by qNMR, ¨100%). 11-1NMR (CDC13): 6 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H), 2.31 (tt, J
=6.4, 2.2 Hz, 2H), 2.36 (t, J =2.2 Hz, 2H), 10.19 (s, 1H).
Example 4: Synthesis of 2-(4-chloropheny1)-4,4-dimethyleyelohex-1-enecarbaldehyde (Compound (G)) [00140] To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL).
The mixture was stirred at 20 C for 5 min. 21.0 wt% K2CO3 aq. solution (76.0 g) was added.
The mixture was stirred at room temperature (ii) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N2 for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2. The reaction
In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d), (0, (g), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 1 comprises steps (a), (b), (d), (e), (0, (g), (h), (i), (j) and (k).
[0034[ Also provided herein is a process for the preparation of Compound 2 of the formula:
HN"..1 Ni o c\N = HN-g =Nv1-1.,,,0e0H
Cl (2) which comprises:
(a) combining a compound of formula (K):
CI (K) wherein R is C1 to C12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L):
0õ
'1\1 (N) CI (L);
(b') combining the compound of formula (L) with a compound of formula (P):
H2N- 411 NH [\,0H
0 (P); and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of formula (2).
[0035] In some embodiments, R is C1 to C6 alkyl. In some embodiments, R is C1 to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and nco-butyl. In some embodiments, R is tut-butyl.
[0036] In one embodiment, the process for the preparation of Compound 2 further comprises:
(c') combining a compound of formula (M):
CI
Oc1ES
NH2 (M) with (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol or a salt thereof, a tertiary amine base, and an organic solvent to provide the compound of formula (P).
[0037] In one embodiment, the (1R,4R)-4-(aminomethyl)-1-methylcyclohexanol salt of step (c') is the p-toluenesulfonic acid salt.
[0038] In some embodiments, the method for the preparation of Compound 2 further comprises step (d) as described above for the preparation of Compound 1.
[0039] In some embodiments, the method for the preparation of Compound 2 further comprises step (e) as described above for the preparation of Compound 1.
[0040] In some embodiments, the method for the preparation of Compound 2 further comprises step (0 and step (g) as described above for the preparation of Compound 1.
[0041] In some embodiments, the method for the preparation of Compound 2 further comprises step (h), step (i), step (j) and step (k) as described above for the preparation of Compound 1.
[0042] In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c') and step (d). In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d) and step (e). In one embodiment, the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d), step (e), step (f) and step (g). In another embodiment the process for the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d), step (e), step (0, step (g), step (h), step (i), step (j) and step (k).
[0043] In one embodiment, the process for the preparation of Compound 2 comprises steps (a), (b') and (d). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d) and (e). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (c'), (d), (h), (i), (j) and (k).
In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (0, (g), (h), (i), (j) and (k). In another embodiment, the process for the preparation of Compound 2 comprises steps (a), (b'), (d), (e), (0, (g), (h), (i), (j) and (k).
[0044] In some embodiments, in step (a) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (a) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step (a) the tert-butoxide salt is potassium tert-butoxide.
[0045] In some embodiments, in step (a) the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (a) the aprotic organic solvent is 2-methyltetrahydrofuran.
[0046] In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (b), step (b') and/or step (b") the organic solvent is dichloromethane.
[0047] In some embodiments, in step (c), step (c') and/or step (c") the tertiary amine base is N,N-diisopropylethylamine.
[0048] In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (c), step (c') and/or step (c") the organic solvent is acetonitrile.
[0049] In some embodiments, in step (d) the compound of formula (I) is first combined with a base prior to the combining of step (d). In some embodiments, the base is an inorganic base.
In some embodiments, the base is an organic base. In some embodiments, the base is selected from the group consisting of K3PO4, Na3PO4, NaOH, KOH, K2CO3 or Na2CO3. In some embodiments, the base is K31304. In some embodiments, in step (d) the compound of formula (I) is first combined with a base in one or more solvents prior to the combining of step (d).
[0050] In some embodiments, in step (d) the source of palladium is Pd2dba3 or [(cinnamyl)PdC1]2. In some embodiments, in step (d) the source of palladium is Pd2dba3.
[0051] In some embodiments, in step (d) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0052] In some embodiments, in step (d) the tert-butoxide salt is anhydrous. In some embodiments, in step (d) the tert-butoxide salt is anhydrous sodium tert-butoxide.
[0053] In some embodiments, in step (d) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (d) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof In some embodiments, in step (d) the aprotic organic solvent is a mixture of THF and toluene.
[0054] In some embodiments, step (d) further comprises the following steps:
(1) combining the tert-butoxide salt with the compound of formula (I) in an aprotic organic solvent;
(2) combining the source of palladium, the compound of formula (J), and the compound of formula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).
[0055] In some embodiments, in step (d) the mixture resulting from step (2) is filtered prior to step (3).
[0056] In some embodiments, step (d) is carried out under an atmosphere of nitrogen or argon.
[0057] In some embodiments, in step (d) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd2dba3 and the catalytic amount of Pd2dba3 is from about 0.5 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of Pd2dba3 is about 0.75 mole percent.
[0058] In some embodiments, in step (d) a catalytic amount of the compound of formula (J) is used relative to the amount of compound (I). In some embodiments, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 2 mole percent.
In one embodiment, the catalytic amount of the compound of formula (J) is about 1 mole percent or about 2 mole percent.
[0059] In some embodiments, in step (e) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (e) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step (e) the tert-butoxide salt is potassium tert-butoxide.
[0060] In some embodiments, in step (e) the organic solvent is selected from the group consisting of pentane, hexane, hcptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1 -butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (e) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (e) the organic solvent is DMF.
[0061] In some embodiments, in step (f), RI is C1 to C4 alkyl. In some embodiments, Rl is isopropyl.
[0062] In some embodiments, in step (f), R is methyl and the Ci to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, R is ethyl and the C1 to C12 alkyl chloroformate is ethyl chloroformate. In some embodiments, R is tert-butyl and the di-(Ci to alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0063] In some embodiments, in step (f) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxanc, nitromethanc, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (f) the aprotic organic solvent is THF.
[0064] In some embodiments, in step (i) the source of palladium is Pd(OAc)2.
[0065] In some embodiments, in step (i) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is acetonitrile.
[0066[ In some embodiments, step (i) comprises combining tetrabutylammonium bromide with the compound of formula (F), a source of palladium and 4-chlorophenylboronic acid in the organic solvent.
[0067] In some embodiments, in step (j) the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (j) the organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (j), the organic solvent is a mixture of THF and toluene.
In some embodiments, the mixture of THF and toluene is about 1:1 by volume.
[0068] In some embodiments, step (j) further comprises producing the compound of formula (H) as a crystalline solid. In some embodiments, step (j) further comprises:
(1) adding an aqueous solution to the mixture of step (j) to produce an aqueous and an organic phase;
(2) separating the organic phase from the mixture of step (1);
(3) concentrating the organic phase; and (4) adding an organic solvent to the mixture of step (3) to produce the compound of formula (H) as a crystalline solid.
[0069] In some embodiments of step (4) of step (j), the organic solvent is acetonitrile. In some embodiments of step (4) of step (j), the organic solvent is acetonitrile and the mixture is heated to about 80 'C.
[0070] In some embodiments, step (4) of step (j) further comprises cooling the mixture to about 10 C to about -10 C. In some embodiments, step (4) of step (j) further comprises cooling the mixture to about -10 C, and isolating the compound of formula (H) as a crystalline solid by filtering the mixture.
[0071] In some embodiments, the combining of step (k) is in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1 -propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the organic solvent is isopropanol.
[0072] In some embodiments, step (k) further comprises producing the compound of formula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in an organic solvent, and step (k) further comprises isolating the compound of formula (I) as a crystalline solid by filtering the mixture.
[0073] In some embodiments, the combining of step (k) is in an organic solvent, and step (k) further comprises cooling the mixture to about 10 C to about -10 C to produce the compound of formula (I) as a crystalline solid.
[0074] In some embodiments, the combining of step (k) is in isopropanol, and step (k) further comprises cooling the mixture to about 10 C to about -10 C to produce the compound of formula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in isopropanol, and step (k) further comprises cooling the mixture to about -5 C
to produce the compound of formula (I) as a crystalline solid, and isolating the compound of formula (I) as a crystalline solid by filtering the mixture.
[0075] Also provided herein is a process of preparing a compound of formula (C):
F
Br (C) wherein R is C1 to C12 alkyl, which comprises (a) combining a compound of formula (A):
is F
Br (A) with RiMgX in an aprotic organic solvent; wherein Rl is CI to C6 alkyl; and X
is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
[0076] In some embodiments, R is C1 to C6 alkyl. In some embodiments, R is C1 to C4 alkyl.
In some embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.
[0077] In some embodiments, RI is C1 to C4 alkyl. In some embodiments, Rl is isopropyl.
[0078] In some embodiments of the process of preparing a compound of formula (C), the organic solvent of step (a) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments the organic solvent of step (a) is THF.
[0079] In one embodiment, R is C1 to C6 alkyl.
[0080] In one embodiment, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.
[0081] In one embodiment, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl; and 121 is isopropyl.
[0082] In one embodiment, R is tert-butyl and RI- is isopropyl.
[0083] In some embodiments of the process of preparing a compound of formula (C), in step (b), R is methyl and the C1 to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, R is ethyl and the C1 to C12 alkyl chloroformate is ethyl chloroformate. In some embodiments, R is tert-butyl and the di-(Ci to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0084] Also provided herein is a process for the preparation of a compound of formula (D):
Br (D) wherein R is C1 to C12 alkyl, which comprises:
(x) combining a compound of formula (B):
HOrrs N
H (B);
with a compound of formula (C):
F
Br (C) and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
[0085] In one embodiment, R is tert-butyl.
[0086] In some embodiments, the process of preparing the compound of formula (D) further comprises steps (x') and (x"):
(x') combining a compound of formula (A):
F
Br (A) with RiMgX in an aprotic organic solvent; wherein R' is C1 to C6 alkyl; and X
is Cl, Br or I;
(x") combining a C1 to C12 alkyl chloroformate or a di-(Ci to C12 alkyl)dicarbonate with the product of step (x'), to provide the compound of formula (C).
[0087] In some embodiments, in step (x) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0088] In some embodiments, the organic solvent of step (x) is selected from the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the organic solvent of step (x) is DMF.
[0089] In some embodiments, in step (x'), RI- is a C1 to C4 alkyl. In some embodiments, RI is isopropyl.
[0090] In some embodiments, in step (x"), the C1 to C12 alkyl chloroformate is methyl chloroformate. In some embodiments, the C1 to C12 alkyl chloroformate is ethyl chloroformate.
In some embodiments, the di-(Ci to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
[0091] In some embodiments, in step (x') the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, in step (x') the aprotic organic solvent is THF.
[0092] Also provided herein is a compound of the formula (3):
HNIr ) N
\N =CO2tBu CI
[0093] In one embodiment, the compound of the formula (3) is prepared by the following steps:
(y) combining a compound of formula (B):
HO
H (B);
with a compound of formula (C):
F
Br (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D):
Br (D), wherein R is tert-butyl; and (z) combining the compound of formula (D), wherein R is tert-butyl;
with a compound of formula (I):
(N) 2HCI
CI (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent.
[0094] In one embodiment, the phosphine ligand of step (z) is a compound of formula (J):
>LIDJ
NMe2 [0095] In other embodiments, the phosphine ligand is selected from:
>W<
)1=., ___________________________________ Br +
¨\04-P'P
\
/.+C)9 Fe Br + Fe Pd BF4 7c I\
[0096] In one embodiment, in step (z) the source of palladium is Pd2dba3.
[0097] In some embodiments, in step (z) the aprotic organic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THE, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the aprotic organic solvent is is a mixture of THF and toluene.
[0098] In some embodiments, in step (z), the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.
[0099] In some embodiments, in step (z) the tert-butoxide salt is anhydrous sodium tert-butoxide or anhydrous potassium tert-butoxide.
[00100] In some embodiments, step (z) further comprises the following steps:
(1) combining the tert-butoxide salt with the compound of formula (I) in an aprotic organic solvent;
(2) combining the source of palladium, the compound of formula (J), and the compound of formula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).
[00101] In some embodiments, in step (z) the mixture resulting from step (2) is filtered prior to step (3).
[00102] In some embodiments, step (z) is carried out under an atmosphere of nitrogen or argon.
[00103] In some embodiments, in step (z) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd2dba3 and the catalytic amount of Pd2dba3 is from about 0.5 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of Pd2dba3 is about 0.75 mole percent.
[00104] In some embodiments, when the phosphine ligand of step (z) is a compound for formula (J), a catalytic amount of the compound of formula (J) is used relative to the amount of compound (1). In some embodiments, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of the compound of formula (J) is about 1 mole percent or about 2 mole percent.
[00105] In another embodiment, provided herein are compounds of the formulae:
HNrsµk N/
\_ CO2tBu 0 =
N/--\N CO2tBu N
Br and CI
[00106] In some embodiments, the processes described herein are improved methods for commercial chemical manufacturing of Compound 1 or Compound 2. Without being bound to a particular theory or mechanism of action, the processes described herein significantly improve the overall efficiency and product yield of Compound 1 or Compound 2. Previous processes (e.g., U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and International Patent Publication Nos. WO 2011/15096 and WO 2012/071336) were found to lack feasibility for production of Compound 1 on a commercial scale. Thus, the processes provided herein represent improved methods for the synthesis of compounds in quantities required for clinical and/or commercial development. Improvements relative to these previous processes include, but are not limited to, overall yield of Compound 1 or Compound 2, overall process efficiency and economics, mild reaction conditions, practical isolation/purification procedures, and viability for commercialization.
[00107] The improved process provided herein involves a selective nucleophilic aromatic substitution reaction ("SnAr reaction") of compounds (B) and (C), which can be carried out under milder conditions with a shorter reaction time when compared to previously described processes as found, for example, in U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and International Patent Publication Nos. WO 2011/15096 and WO
2012/071336. Without being limited by theory, the improved SnAr reaction of compound (B) and (C) does not generate regioisomeric side products which necessitate further purification to remove the side products, as was the case in previously described processes.
The SnAr reaction in the previous process also requires a longer reaction time and harsh reaction conditions which result in a low overall yield relative to the processes described herein.
Furthermore, the previous processes also require tedious purification of the intermediates which is impracticable on a large, commercial scale process. The processes described herein are more convergent than prior processes, resulting in a highly efficient cross-coupling reaction of compound (D) and the free base of compound (I) in high yield. In some embodiments, the processes described herein utilize crystalline solid intermediates (H) and (I), which allow efficient purification by crystallization to remove impurities ¨ advantages not available in previously described processes.
[00108] The following schemes illustrate one or more embodiments of the process provided herein. In some embodiments, the compound of formula (D) is prepared from compound (B) and compound (C) as shown in Scheme 1 below. The compound of formula (B) may be prepared by techniques known in the art, e.g., as shown in WO 2000/047212 and I Am. Chem.
Soc., 1959, 81: 743-747. The compound of formula (C) may be prepared by techniques known in the art, e.g., as shown in WO 2006/059801 and Tetrahedron Letters, 2008, 49(12), 2034-2037;
or as shown in Scheme 2.
Scheme 1 F
HOrn = CO2R
N Br =
N N
KOtBu / DMF Br [00109] The compound of formula (C) of Scheme 1 may prepared from commercially available compound (A) as shown in Scheme 2 below, wherein "RiMgX" represents a Grignard reagent wherein Rl is an alkyl group, and X is Cl, Br or I. The electrophilic acetylating reagent of Scheme 2 can be, but is not limited to, methyl or ethyl chloroformate or BOC20.
Scheme 2 1. RiMgBr 002R
F 2. Electrophilic acylating reagent F
Br Br A
[00110] An exemplary reaction according to Scheme 2 is shown below.
1. iPrMgBr CO2tBu ioF 2. Boc20 F
Br Br [00111] In another embodiment, the compound of formula (I) is prepared from compound (E) as shown in Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. 3,813,443 and Proceedings of the Chemical Society, London, 1907, 22, 302.
Scheme 3 9 Boc Boc OH
9 gi B.OH j THF,N) CNJ
DMF, POCI3 N tolunene HCI, IPA
0 CI 4111"
Pd(OAc)2 CI
MeCN
CI
CI
[00112] In another embodiment, the compound of formula (N) is prepared from compound (M) as shown in Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 and J. Am. Chem.
Soc., 1950, 72, 1215-1218.
Scheme 4 H2Ni ( -3 NO2 NO2 H
cl el CI MeCN, DIEA Q
[00113] In another embodiment, the compound of formula (P) is prepared from compound (M) as shown in Scheme 4' below.
Scheme 4' CH3MgBr Toluene ir I-110 HCI
-b. HC[1 i:;,1 1 Toluene, 80 C
H2N/--\N,., I' õ
Alb.
illi 0 0 _20 _ 30 C 0 0 \__/ \__/ 0 I
ON
el.,PCy3 lc HO
[I HO,,.
0 PF6 ...--1) RaNi, wet! H2 Crabtree's cat. THF
________________________________________ p¨
DCM, 30 C 2) MeCN / pTSA
02N pTSA H2N
dr > 99%
HO,,, 1:1 (3%
0-.2S% NO2 0 CI MeCN, DIEA
+
_________________________________________ - H2N¨S 4. N OH
H
8 .
pTSA H2N m [00114] In another embodiment, the compound of formula (1) is prepared from compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in WO 2009/117626 and Organometallies, 2008, 27(21), 5605-5611.
Scheme 5 co2R
. n N.- N CO2R CO2H
H
Br D > 0 orn LiDk 0 oT
N' N
+ z 01 J N N
H N H
NMe2 (N) baseND L
H -,-(1\1 ,1 2HCI K
Pd2dba3 -0tBu (1 CI CI
CI I
CO2H 9 =
0=S
() 0 NH
EDAC, DMAP
(N) ,H2,12 CI L (1) CI
[00115] In another embodiment, the compound of formula (2) is prepared from compound (L) and compound (P) as shown in Scheme 6 below, wherein the preparation of compound (P) is as shown in Scheme 4' and the preparation of compound (L) is as shown in Scheme 5.
Scheme 6 H
op 0 NH
-s NO2 C
d EDAC, DMAPOOH
NH
CH2Cl2 CI L (2) CI
[00116] In some embodiments, the preparation of the compound of formula (K) from compound (D) and compound (I) is air and/or moisture sensitive, and is therefore performed under an inert atmosphere, e.g., using nitrogen or argon gas.
[00117] Without being bound to a particular theory, the use of compound (D) as an intermediate in the preparation of the compound of formula (1) and the compound of formula (2) as shown above in Schemes 1 to 6 is an improvement over previously described processes for the preparation of the compound of formula (1) and the compound of formula (2). In some embodiments, the improvements include higher product yields, shorter reaction times. In some embodiments, the improvements are provided when R is tert-butyl in compound (D).
[00118] Schemes 1 to 6 are non-limiting examples of the process provided herein. Solvents and/or reagents are known compounds and may be interchanged according to the knowledge of those skilled in the art.
[00119] Abbreviations used in Schemes 1 to 6 are as follows:
Ac acetyl BOC tert-butoxycarbonyl dba dibenzylidineacetone DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide EDAC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 IPA isopropanol iPr isopropyl Me methyl n-Bu n-butyl tBu tert-butyl THF tetrahydrofuran [00120] Unless indicated otherwise, the temperatures at which a reaction of Schemes 1 to 6 is conducted is not critical. In certain embodiments, when a temperature is indicated in a reaction, the temperature may be varied from about plus or minus 0.1 C, 0.5 C, 1 C, 5 C, or 10 C.
Depending upon which solvent is employed in a particular reaction, the optimum temperature may vary. In some embodiments, reactions are conducted in the presence of vigorous agitation sufficient to maintain an essentially uniformly dispersed mixture of the reactants.
[00121] In conducting a reaction provided herein, neither the rate, nor the order, of addition of the reactants is critical unless otherwise indicated. Unless otherwise indicated, reactions are conducted at ambient atmospheric pressure. Unless otherwise indicated, the exact amount of reactants is not critical. In some embodiments, the amount of a reactant may be varied by about mole percent or about 10% by weight.
[00122] Unless otherwise indicated, the organic solvents used in the processes provided herein may be selected from those commercially available or otherwise known to those skilled in the art. Appropriate solvents for a given reaction are within the knowledge of the skilled person and include mixtures of solvents. Examples of organic solvents provided herein for use include but are not limited to: pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran (THF), dimethylformamide (DMF), hexamethylphosphoramide (HMPA), N-methyl-2-pyrrolidinone (NMP), nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof.
[00123] In some embodiments, an organic solvent used in the processes provided herein is an aprotic organic solvent. As provided herein, an aprotic solvent is a solvent that does not contain an acidic hydrogen atom or a hydrogen atom that is capable of hydrogen bonding (e.g., is not bound to an oxygen or a nitrogen atom). The aprotic organic solvent may be selected from the group consisting of dichloromethane, chloroform, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, the aprotic organic solvent is THF. In some embodiments, the aprotic organic solvent is DMF. In some embodiments, the aprotic organic solvent is acetonitrile.
[00124] As provided herein, a "tertiary amine base" refers to an amine that is substituted with three alkyl groups, e.g., triethylamine or N,N-diisopropyl ethyl amine.
[00125] As provided herein, a "catalytic amount" refers to less than one molar equivalent of a reagent or reactant in a given reaction, as determined relative to another reagent or reactant in the reaction mixture. In some embodiments, a catalytic amount is described as a mole percent relative to another reagent or reactant in the reaction mixture.
[00126] As provided herein, a "source of palladium" refers to a source of palladium in a stable oxidation state, i.e., Pd(0), Pd(I), Pd(II) and/or Pd(IV). The palladium may be free metal, such as in a powder form, or may be bound to one or more ligands, e.g., PdC12, Pd2dba3, PdC12(PPh3)2, Pd(PPh3)4, Pd(OAc)2 or [(cinnamyl)PdC1]2.
[00127] As provided herein, a "phosphine ligand" refers to a compound of formula PR'1, wherein each R' is independently selected from CI to C6 alkyl or phenyl, wherein the aryl group is optionally substituted by C1 to C6 alkyl, phenyl, trialkylamino, alkoxy or halo.
[00128] As provided herein, unless otherwise defined, the term "about" means that the value or amount to which it refers can vary by 5%, 2%, or 1%.
[00129] The products obtained by any of the processes provided herein may be recovered by conventional means, such as evaporation or extraction, and may be purified by standard procedures, such as distillation, recrystallization or chromatography EXAMPLES
[00130] Compounds of the following examples are shown in Schemes 1 to 6 above and were named using Chemdraw0 Ultra software. In addition to the abbreviations described above with respect to the schemes provided herein, the following abbreviations are used in the Examples:
[00131] "HPLC" = high pressure liquid chromatography; "IP" = in process; "ML"
= mother liquor; "NLT" = no less than; "NMT" = no more than; "RB" = round bottom; "RT"
= room temperature; "sm" = starting material; "DCM" = dichloromethane.
[00132] Unless indicated otherwise, compounds were characterized by HPLC and analysis and used in later reactions with or without purification. 1H NMR
analysis was perfoimed at 400 MHz unless otherwise indicated. Unless specified otherwise, product yield/purity was determined by weight, qNMR, and/or HPLC analysis.
Example 1: Synthesis of tert-butyl 4-bromo-241uorobenzoate (Compound (C)) [00133] To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro 1 -iodobenzene, "Compound (A)" (5 g, 1.0 eq) and THF (25 m1).
The solution was cooled to -5 C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0 C. The mixture was stirred at 0 C for 1 h.
Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10 % citric acid (10 ml), and then diluted with 25 % NaC1 (10 m1). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3 x m1). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency = 67%, potency adjusted yield = 88%) was taken to the next step without further purification. Ili NMR (DMSO-d6): 6 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H),7.74 (t, J= 8.2 Hz, 1H).
Example 2: Synthesis of tert-butyl 2-41H-pyrrolo[2,3-b]pyridin-5-y0oxy)-4-bromobenzoate (Compound (D)) [00134] To a 3 L three-neck Morton flask were charged 1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20 C for 15 min. The resulting solution was cooled to about zero to 5 'C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10 C, and rinsed with DMF (30 mL). The reaction mixture was stirred at 10 'V for 1 hour (an off-white slurry) and adjusted the internal temperature to - 45 C over 30 min. The reaction mixture was stirred at 45-50 C for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion %
by HPLC).
The solution was cooled to - 20 C. The solution was stirred at 20 C
overnight.
[00135] Water (1200 mL) was added slowly to the reaction mixture at <30 C
over lhour (slightly exothermic). The product slurry was adjusted to - 20 C, and mixed for NLT 2 hours.
The crude product was collected by filtration, and washed with water (400 naL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50 C overnight to give the crude product (236.7g).
[00136] Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted:
200.7 g) was charged back to a 3L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over lhr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78 C). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to - -10 C at a rate of approximate 10 C/hour), and mixed for 2hr. The product was collected by filtration, and rinsed with heptane (200 m1).
[00137] The solid was dried under vacuum at - 50 C overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191 C
(uncorrected).
1H NMR (DMSO-d6): 6 1.40 (s, 9H), 6.41 (dd, J= 3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J= 8.3, 1.8 Hz, 1H), 7.51 (t, J= 3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
Example 3: Synthesis of 2-ehloro-4,4-dimethyleyelohexanecarbaldehyde (Compound (F)) [00138] To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456mo1) and (80 mL). The solution was cooled down <-5 C, and P0C13 (64.7 g, 0.422 mol) added slowly over 20 min (ci) <20 C (exothermic), rinsed with CH2C12 (6 mL). The slightly brown solution was adjusted to 20 C over 30 min, and mixed at 20 C for 1 hour. The solution was cooled back to < 5 C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ¨0.292 mol) was added, and rinsed with in CH2C12 (10 mL) (slightly exothermic) at <20 'V The solution was heated to refluxing temperature, and mixed overnight (21 hours.).
[00139] To a 1000 mL three neck RB flask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12%
brine, and 130 mL
of CH2C12. The mixture was stirred and cooled down to <5 C. The above reaction mixture (clear and brown) was transferred, quenched into it slowly while maintaining the internal temperature <10 C. The reaction vessel was rinsed with CH2C12 (10 mL). The quenched reaction mixture was stirred at <10 C for 15 min. and allowed to rise to 20 C. The mixture was stirred 20 'V for 15 min and allowed to settle for 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extracted with CH2C12 (50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K3PO4 aq. solution (40 g). The organic was dried over MgSO4, filtered and rinsed with CH2C12 (30 ml). The filtrate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency=90.9wt% by qNMR, ¨100%). 11-1NMR (CDC13): 6 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H), 2.31 (tt, J
=6.4, 2.2 Hz, 2H), 2.36 (t, J =2.2 Hz, 2H), 10.19 (s, 1H).
Example 4: Synthesis of 2-(4-chloropheny1)-4,4-dimethyleyelohex-1-enecarbaldehyde (Compound (G)) [00140] To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL).
The mixture was stirred at 20 C for 5 min. 21.0 wt% K2CO3 aq. solution (76.0 g) was added.
The mixture was stirred at room temperature (ii) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N2 for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2. The reaction
-34-mixture was evacuated and purged with N2 for three times (an orange colored mixture). The bottle was back filled with N2 and heated to ¨35 C in an oil bath (bath temp ¨35 C). The mixture was stirred at 30 'V overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material < 2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO3-2% L-Cysteine aq.
solution (100 mL) were added. The mixture was stirred at 20 'V for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ¨1/3 volume (¨ 35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. 11INMR (CDC13): 6 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
Example 5: Synthesis of tert-butyl 4-44'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-yl)methyl)piperazine-1-earboxylate (Compound (H)) [00141] To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-carbaldehyde (50.0g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20 C for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ¨29.5 C in 15 min cooling may be needed). The yellow mixture was stirred at ¨ 25 C for NLT 4hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
[00142] 12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20 'V for NLT 30 min and allowed to settle for NLT 15 min. The lower aq. phase (-560 mL) was separated (note: leave any emulsion in the upper organic phase).
The organic phase was washed with 10% citric acid solution (500 g x2). 500 g of 5% NaHCO3 aq. solution was charged slowly into the flask. The mixture was stirred at 20 C for NLT 30 min., and allowed to settle for NLT 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20 C for NLT 15 min., and allowed to
solution (100 mL) were added. The mixture was stirred at 20 'V for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ¨1/3 volume (¨ 35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. 11INMR (CDC13): 6 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).
Example 5: Synthesis of tert-butyl 4-44'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-yl)methyl)piperazine-1-earboxylate (Compound (H)) [00141] To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-carbaldehyde (50.0g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20 C for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ¨29.5 C in 15 min cooling may be needed). The yellow mixture was stirred at ¨ 25 C for NLT 4hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
[00142] 12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20 'V for NLT 30 min and allowed to settle for NLT 15 min. The lower aq. phase (-560 mL) was separated (note: leave any emulsion in the upper organic phase).
The organic phase was washed with 10% citric acid solution (500 g x2). 500 g of 5% NaHCO3 aq. solution was charged slowly into the flask. The mixture was stirred at 20 C for NLT 30 min., and allowed to settle for NLT 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20 C for NLT 15 min., and allowed to
-35-settle for NLT 15 min. The upper organic phase was concentrated to ¨ 200 ml, volume under vacuum. The solution was adjusted to ¨ 30 C, and filtered off the inorganic salt. Toluene (50 mL) was used as a rinse. The combined filtrate was concentrated to ¨100 mL
volume.
Acetonitrile (400 mL) was added, and the mixture heated to ¨ 80 C to achieve a clear solution.
The solution was cooled down slowly to 20 'V slowly at rate 10 C/hour, and mixed at 20 C
overnight (the product is crystallized out at ¨45-50 'V, if needed, seed material may be added at 50 C). The slurry was continued to cool down slowly to ¨ -10 C at rate of 10 C/hours. The slurry was mixed at ¨ -10 C for NLT 6 hours. The product was collected by filtration, and rinsed with pre-cooled acetonitrile (100mL). The solid was dried under vacuum at 50 C overnight (72.0 g, 85%). MS-ESI: 419 (M+1); mp: 109-110 C (uncorrected); 1H NMR (CDC13):
6 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).
Example 6: Synthesis of 1-44'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-y1)methyl)piperazine dihydrochloride (Compound (I)) [00143] To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the Boc reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3g of concentrated hydrochloride aq. solution added to the slurry.
The reaction mixture was adjusted to an internal temperature of ¨ 65 C (a clear and colorless solution achieved). The reaction mixture was agitated at ¨ 65 C for NLT 12 hours.
[00144] The product slurry was cooled down to -5 C slowly (10 C/hour). The product slurry was mixed at ¨ -5 C for NLT 2 hours, collected by filtration. The wet cake was washed with IPA (72 mL) and dried at 50 'V under vacuum overnight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm). MS-ESI: 319 (M+1); 11-INMR (D20): 6 1.00 (s, 6H), 1.19 (d, J=6.0 Hz, 6H, IPA), 1.65 (t, J=6.1 Hz, 2H), 2.14 (s, br, 2H), 2.26 (m, 2H), 3.36 (br, 4H), 3.55 (s, br, 4H), 3.82 (s, 2H), 4.02 (septet, J=6.0 Hz, 1H, IPA), 7.16 (d, ,J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H); 1HNMR (CDC13): 60.86 (s, 6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).
volume.
Acetonitrile (400 mL) was added, and the mixture heated to ¨ 80 C to achieve a clear solution.
The solution was cooled down slowly to 20 'V slowly at rate 10 C/hour, and mixed at 20 C
overnight (the product is crystallized out at ¨45-50 'V, if needed, seed material may be added at 50 C). The slurry was continued to cool down slowly to ¨ -10 C at rate of 10 C/hours. The slurry was mixed at ¨ -10 C for NLT 6 hours. The product was collected by filtration, and rinsed with pre-cooled acetonitrile (100mL). The solid was dried under vacuum at 50 C overnight (72.0 g, 85%). MS-ESI: 419 (M+1); mp: 109-110 C (uncorrected); 1H NMR (CDC13):
6 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).
Example 6: Synthesis of 1-44'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-y1)methyl)piperazine dihydrochloride (Compound (I)) [00143] To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the Boc reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3g of concentrated hydrochloride aq. solution added to the slurry.
The reaction mixture was adjusted to an internal temperature of ¨ 65 C (a clear and colorless solution achieved). The reaction mixture was agitated at ¨ 65 C for NLT 12 hours.
[00144] The product slurry was cooled down to -5 C slowly (10 C/hour). The product slurry was mixed at ¨ -5 C for NLT 2 hours, collected by filtration. The wet cake was washed with IPA (72 mL) and dried at 50 'V under vacuum overnight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm). MS-ESI: 319 (M+1); 11-INMR (D20): 6 1.00 (s, 6H), 1.19 (d, J=6.0 Hz, 6H, IPA), 1.65 (t, J=6.1 Hz, 2H), 2.14 (s, br, 2H), 2.26 (m, 2H), 3.36 (br, 4H), 3.55 (s, br, 4H), 3.82 (s, 2H), 4.02 (septet, J=6.0 Hz, 1H, IPA), 7.16 (d, ,J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H); 1HNMR (CDC13): 60.86 (s, 6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).
-36-Example 7: Synthesis of 3-nitro-4-(((tetrahydro-211-pyran-4-yl)methyl)amino)-benzenesulfonamide (Compound (N)) [00145] To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80 C and agitated for no less than 12 hours.
[00146] The product solution was cooled down to 40 C and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20 'C.
Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 'V and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40 C for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75 C under vacuum to give 12.7 g of the desired product in 99.9%
purity and in 91%
weight-adjusted yield. 1H NMR (DMSO-d6): 6 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH2, 2H), 7.81(dd, J=9.1 , 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).
Example 8: Synthesis of tert-butyl 2-41H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-44'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-y1)methyl)piperazin-1-y1)benzoate (Compound (K)) [00147] General Considerations: this chemistry is considered air and moisture sensitive.
While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.
[00148] To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K3PO4 (285 ml) was
[00146] The product solution was cooled down to 40 C and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20 'C.
Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 'V and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40 C for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75 C under vacuum to give 12.7 g of the desired product in 99.9%
purity and in 91%
weight-adjusted yield. 1H NMR (DMSO-d6): 6 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH2, 2H), 7.81(dd, J=9.1 , 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).
Example 8: Synthesis of tert-butyl 2-41H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-44'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-y1)methyl)piperazin-1-y1)benzoate (Compound (K)) [00147] General Considerations: this chemistry is considered air and moisture sensitive.
While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.
[00148] To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K3PO4 (285 ml) was
-37-added and the biphasic mixture was stirred for 30 min. The layers were separated and the organic layer was washed with 25 % NaCl (145 m1). The organic layer concentrated to 120 g and used in the coupling reaction without further purification.
[00149] NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution -30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd2dba3 (0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 !um inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml.).
[00150] The resulting mixture was heated to 55 C with stirring for NLT 16 h, then cooled to 22 C. The mixture was diluted with 12% NaC1 (300 g) followed by THF (300 ml).
The layers were separated.
[00151] The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 m1). After 1 h the layers were separated.
[00152] The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 m1). After 1 h the layers were separated. The organic layer was washed with 12 % NaC1 (300 g), then filtered through a 0.45 i.tm inline filter. The filtered solution was concentrated in vacuo to - 300 mL, and chased three times with heptane (600 mL each) to remove THF.
[00153] The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 m1). The mixture was heated to 75 C, held for 15 min, and then cooled to 65 C over NLT 15 min. Seed material was charged and the mixture was held at 65 C for 4 hours.
The suspension was cooled to 25 C over NLT 8 h, then held at 25 C for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50 C under vacuum.
[00154] Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155 C. 1H NMR (DMSO-d6): 6 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J= 6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02- 3.19 (m, 4H), 6.33 (dd, J= 3.4, 1.9 Hz, 1H), 6.38 (d, 2.4 Hz, 1H), 6.72 (dd, J= 9.0, 2.4 Hz, 1H), 6.99 - 7.06 (m, 2H), 7.29 (d, J=
2.7 Hz, 1H), 7.30 -7.36 (m, 2H), 7.41 -7.44 (m, 1H), 7.64 (t, J= 6.7 Hz, 1H), 7.94 (d, J= 2.7 Hz, 1H), 11.53 (s, 1H).
[00149] NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution -30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd2dba3 (0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 !um inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml.).
[00150] The resulting mixture was heated to 55 C with stirring for NLT 16 h, then cooled to 22 C. The mixture was diluted with 12% NaC1 (300 g) followed by THF (300 ml).
The layers were separated.
[00151] The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 m1). After 1 h the layers were separated.
[00152] The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 m1). After 1 h the layers were separated. The organic layer was washed with 12 % NaC1 (300 g), then filtered through a 0.45 i.tm inline filter. The filtered solution was concentrated in vacuo to - 300 mL, and chased three times with heptane (600 mL each) to remove THF.
[00153] The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 m1). The mixture was heated to 75 C, held for 15 min, and then cooled to 65 C over NLT 15 min. Seed material was charged and the mixture was held at 65 C for 4 hours.
The suspension was cooled to 25 C over NLT 8 h, then held at 25 C for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50 C under vacuum.
[00154] Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155 C. 1H NMR (DMSO-d6): 6 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J= 6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02- 3.19 (m, 4H), 6.33 (dd, J= 3.4, 1.9 Hz, 1H), 6.38 (d, 2.4 Hz, 1H), 6.72 (dd, J= 9.0, 2.4 Hz, 1H), 6.99 - 7.06 (m, 2H), 7.29 (d, J=
2.7 Hz, 1H), 7.30 -7.36 (m, 2H), 7.41 -7.44 (m, 1H), 7.64 (t, J= 6.7 Hz, 1H), 7.94 (d, J= 2.7 Hz, 1H), 11.53 (s, 1H).
-38-Example 9: Synthesis of 2-41H-pyrrolo[2,3-b[pyridin-5-yl)oxy)-4-(4-04'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1X-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (Compound (L)) [00155] Solution preparation: 10% KH2PO4 (aq): KH2PO4 (6 g) in water (56 g);
2:1 heptane / 2-MeTHF : heptane (16 mL) in 2-MeTHF (8 mL).
[00156] Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55 C until reaction completion. The reaction mixture was cooled to 22 C, washed with the 10% KH2PO4 solution (31 g) twice. The organic layer was then washed with water (30 g).
[00157] After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (-19 mL) and heated to no less than 50 C. Heptane (23 ml) was slowly added.
Alternatively, after removal of the aqueous layer, the organic layer was concentrated to 5 volumes and heated to no less than 70 C and 5 volumes of heptane were slowly added. The resulting suspension was cooled to 10 C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane / 2-MeTHF (24 m1). Drying of the solids at 80 C under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. 1FI NMR (DMSO-d6): 60.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J= 9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J= 3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
Example 10: Synthesis of 4-(4-1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-yl]methyllpiperazin-1-y1)-N-(13-nitro-4-[(tetrahydro-211-pyran-4-ylmethyl)amino]phenyllsulfonyl)-2-(1H-pyrrolo[2,3-13]pyridin-5-yloxy)benzamide (Compound (1)) [00158] Solution preparation prior to reaction: 10% Acetic Acid: Acetic Acid (37 mL) in water (333 g); 5% NaHCO3: NaHCO3 (9 g) in water (176 g); 5% NaC1 : NaCl (9 g) in water (176 g).
[00159] Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25 C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et3N (8.7 g) and dichloromethane (120 mL). The
2:1 heptane / 2-MeTHF : heptane (16 mL) in 2-MeTHF (8 mL).
[00156] Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55 C until reaction completion. The reaction mixture was cooled to 22 C, washed with the 10% KH2PO4 solution (31 g) twice. The organic layer was then washed with water (30 g).
[00157] After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (-19 mL) and heated to no less than 50 C. Heptane (23 ml) was slowly added.
Alternatively, after removal of the aqueous layer, the organic layer was concentrated to 5 volumes and heated to no less than 70 C and 5 volumes of heptane were slowly added. The resulting suspension was cooled to 10 C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane / 2-MeTHF (24 m1). Drying of the solids at 80 C under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. 1FI NMR (DMSO-d6): 60.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J= 9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J= 3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
Example 10: Synthesis of 4-(4-1[2-(4-chloropheny1)-4,4-dimethylcyclohex-1-en-l-yl]methyllpiperazin-1-y1)-N-(13-nitro-4-[(tetrahydro-211-pyran-4-ylmethyl)amino]phenyllsulfonyl)-2-(1H-pyrrolo[2,3-13]pyridin-5-yloxy)benzamide (Compound (1)) [00158] Solution preparation prior to reaction: 10% Acetic Acid: Acetic Acid (37 mL) in water (333 g); 5% NaHCO3: NaHCO3 (9 g) in water (176 g); 5% NaC1 : NaCl (9 g) in water (176 g).
[00159] Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25 C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et3N (8.7 g) and dichloromethane (120 mL). The
-39-resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion. N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35 C and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL).
The organic, product layer was then washed with 5% NaHCO3 solution (185 mL) and then washed with 5%
NaC1 solution (185 mL) at 35 C. The lower, organic layer was separated and then concentrated to 8 vol (-256 mL) diluted with methanol (26 mL) and warmed to 38 C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10 C and then filtered.
The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (-2 vol, 64 mL). After drying the wet cake at 90 C, 32 g (84%) of Compound (1) was isolated. 1H NMR
(DMSO-d6): 6 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J= 3.4, 1.9 Hz, 1H), 6.66 (dd, J=
9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J= 9.3, 2.3 Hz, 1H), 8.02 (d, J=2. 61 Hz, 1H), 8.54 (d, J=2. 33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).
Example 11: Synthesis of ((131,4R)-4-hydroxy-4-methylcyclohexyl)-methanaminium 4-methylbenzenesulfonate [00160] Step A: 1.49 g of cyclohexanedione monoethylene acetal (1.0 equiv) and 15 mL of toluene were charged to a suitable reactor. The mixture was mixed for 30 minutes at 10 C. 1.4 M
methylmagnesium bromide solution (2.32 eq) in Toluene-THF (75-25) was charged to another reactor and mixed at 15 C. The starting material solution was added to the Grignard solution dropwise at around 10 to 20 C in 4hrs (addition rate = 0.1mL/min). The reaction progression was monitored by TLC. Upon reaction completion, the reaction mixture was charged to a 24 %
ammonium chloride solution (20 mL) slowly at a temperature of 25oC. The reaction mixture was mixed and settled, organic layer was separated and aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were filtered over a bed of sodium sulfate and the filtrate was concentrated by distillation to dryness. 1.57 g. crude solids were isolated (95%
yield) and carried to the next step. 1H NMR (400 MHz, Chloroform-d1) 6 ppm 3.88-4.01 (m,
The organic, product layer was then washed with 5% NaHCO3 solution (185 mL) and then washed with 5%
NaC1 solution (185 mL) at 35 C. The lower, organic layer was separated and then concentrated to 8 vol (-256 mL) diluted with methanol (26 mL) and warmed to 38 C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10 C and then filtered.
The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (-2 vol, 64 mL). After drying the wet cake at 90 C, 32 g (84%) of Compound (1) was isolated. 1H NMR
(DMSO-d6): 6 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J= 3.4, 1.9 Hz, 1H), 6.66 (dd, J=
9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J= 9.3, 2.3 Hz, 1H), 8.02 (d, J=2. 61 Hz, 1H), 8.54 (d, J=2. 33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).
Example 11: Synthesis of ((131,4R)-4-hydroxy-4-methylcyclohexyl)-methanaminium 4-methylbenzenesulfonate [00160] Step A: 1.49 g of cyclohexanedione monoethylene acetal (1.0 equiv) and 15 mL of toluene were charged to a suitable reactor. The mixture was mixed for 30 minutes at 10 C. 1.4 M
methylmagnesium bromide solution (2.32 eq) in Toluene-THF (75-25) was charged to another reactor and mixed at 15 C. The starting material solution was added to the Grignard solution dropwise at around 10 to 20 C in 4hrs (addition rate = 0.1mL/min). The reaction progression was monitored by TLC. Upon reaction completion, the reaction mixture was charged to a 24 %
ammonium chloride solution (20 mL) slowly at a temperature of 25oC. The reaction mixture was mixed and settled, organic layer was separated and aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were filtered over a bed of sodium sulfate and the filtrate was concentrated by distillation to dryness. 1.57 g. crude solids were isolated (95%
yield) and carried to the next step. 1H NMR (400 MHz, Chloroform-d1) 6 ppm 3.88-4.01 (m,
-40-4H), 1.85-1.96 (m, 2H), 1.08-1.64 (m, 7H). LCMS- (MS 310 and 292). Rf = 0.074 by TLC
(hexane-Et0Ac = 1-1).
[00161] Step B: 18 nit of 0.005 N hydrochloric acid solution (0.02 equiv) was charged to the distillation residue from Step A. The reaction mixture was mixed at 70 C for 3 hours and monitored by TLC. Upon reaction completion, the reaction mixture was cooled to 25 C and charged to another suitable reactor containing 22 mL of a 5% sodium chloride solution. The reaction mixture was mixed until all salt dissolved followed by extraction with Ethyl Acetate (8x200 mL). The combined organic layers were filtered over a bed of sodium sulfate and the filtrate was concentrated by distillation to dryness. The product was isolated (99.38 % yield) and was used directly in the next step. 1H NMR (400 MHz, Chloroform-di) 6 ppm 2.68-2.80 (m, 2H), 2.16-2.39 (m, 3H), 1.77-2.04 (m, 4H), 1.41 (s, 3H), 1.33 (s, 1H).
[00162] Step C: Step B product (0.25 g) was dissolved with toluene (5 ml) to a 25 mL three neck flask equipped with a Dean-Stark trap. Nitrogen was bubbled through the reactor to remove air. 0.585 g of nitromethane (5 equiv) was charged to the reactor followed by 0.052 g of N,N-dimethylethylenediamine (0.3 equiv). The reaction mixture was heated to reflux, the water was removed by a Dean-Stark trap. The reaction mixture was mixed at reflux for 1 h and monitored by HPLC assay. The reaction mixture was then cooled to 20 C when HPLC product assay stabilized, concentrated then chased with Et0Ac and heptane to dryness.
The residue was purified on a CombiFlash column (12 g column) from Hexane/Et0Ac 80-20 to 60-40. Fractions were analyzed by HPLC and TLC, product containing fractions was distilled to dryness. A
concentrated oil 0.23 g was obtained (68.09 % yield) and used in Step D. 1H
NMR (400 MHz, Chloroform-di) 6 5.88-5.90 (bs, 1H), 4.88-4.89 (bs, 2H), 2.16-2.40 (m, 4H), 1.78-1.85 (m, 1H), 1.33 (s, 3H).
[00163] Step D: Crabtree's catalyst (0.471 g; 0.585 mmol) was added under nitrogen to a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen and a solution of the (S)-1-methy1-4-(nitromethyl)cyclohex-3-enol (34.88 g; 58.5 mmol) in DCM (100 mL).
Additional sparged DCM (80 mL) was added, the reactor was purged with argon, hydrogen and hydrogen pressure 100 psig. The mixture was agitated for 4 hours at 30 C. Reaction progress was monitored by NMR, cConcentrated to an oil, chased 2 x with THF (50 mL) then diluted with THF (50 mL). The product was carried further for subsequent RaNi reduction in Step E. 1H
(hexane-Et0Ac = 1-1).
[00161] Step B: 18 nit of 0.005 N hydrochloric acid solution (0.02 equiv) was charged to the distillation residue from Step A. The reaction mixture was mixed at 70 C for 3 hours and monitored by TLC. Upon reaction completion, the reaction mixture was cooled to 25 C and charged to another suitable reactor containing 22 mL of a 5% sodium chloride solution. The reaction mixture was mixed until all salt dissolved followed by extraction with Ethyl Acetate (8x200 mL). The combined organic layers were filtered over a bed of sodium sulfate and the filtrate was concentrated by distillation to dryness. The product was isolated (99.38 % yield) and was used directly in the next step. 1H NMR (400 MHz, Chloroform-di) 6 ppm 2.68-2.80 (m, 2H), 2.16-2.39 (m, 3H), 1.77-2.04 (m, 4H), 1.41 (s, 3H), 1.33 (s, 1H).
[00162] Step C: Step B product (0.25 g) was dissolved with toluene (5 ml) to a 25 mL three neck flask equipped with a Dean-Stark trap. Nitrogen was bubbled through the reactor to remove air. 0.585 g of nitromethane (5 equiv) was charged to the reactor followed by 0.052 g of N,N-dimethylethylenediamine (0.3 equiv). The reaction mixture was heated to reflux, the water was removed by a Dean-Stark trap. The reaction mixture was mixed at reflux for 1 h and monitored by HPLC assay. The reaction mixture was then cooled to 20 C when HPLC product assay stabilized, concentrated then chased with Et0Ac and heptane to dryness.
The residue was purified on a CombiFlash column (12 g column) from Hexane/Et0Ac 80-20 to 60-40. Fractions were analyzed by HPLC and TLC, product containing fractions was distilled to dryness. A
concentrated oil 0.23 g was obtained (68.09 % yield) and used in Step D. 1H
NMR (400 MHz, Chloroform-di) 6 5.88-5.90 (bs, 1H), 4.88-4.89 (bs, 2H), 2.16-2.40 (m, 4H), 1.78-1.85 (m, 1H), 1.33 (s, 3H).
[00163] Step D: Crabtree's catalyst (0.471 g; 0.585 mmol) was added under nitrogen to a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen and a solution of the (S)-1-methy1-4-(nitromethyl)cyclohex-3-enol (34.88 g; 58.5 mmol) in DCM (100 mL).
Additional sparged DCM (80 mL) was added, the reactor was purged with argon, hydrogen and hydrogen pressure 100 psig. The mixture was agitated for 4 hours at 30 C. Reaction progress was monitored by NMR, cConcentrated to an oil, chased 2 x with THF (50 mL) then diluted with THF (50 mL). The product was carried further for subsequent RaNi reduction in Step E. 1H
-41-NMR (Chloroform-di): 6 4.33 (dJ = 7.3Hz, 2H), 4.32 ( J=6.5 Hz, 1H), 2.36 -2.20 (m, 1H), 1.92 -1.69 (m, 1H), 1.64- 1.40 (m, 1H), 1.39- 1.18 (m, 1H).
[00164] Step E: RaNi (* d / (d-1) or * 7/6) = 2.04 g (20 wt%) was decanted 3 times with THF.
The RaNi, solution of (1R,4R)-1-methyl-4-(nitromethyl)cyclohexanol and THF (50 mL) were added under nitrogen in a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen, hydrogen and the hydrogenation was carried out at 40 psi for 4 hours at 50 C.
The reaction was monitored by GC and upon completion, it was filtered through a propylene filter funnel with diatomaceous earth/polyethylene fritted disc to remove catalyst. THF was used as a rinse to extract residual product from the filter cake. The combined filtrate gave an amber solution which was carried directly to next step. 1H NMR (400 MHz, Chloroform-di) 6 2.61 (d, J = 6.5 Hz, 2H), 1.25-1.50 (m, 12H), 0.80-1.17 (m, 3H).
[00165] Step F: 9.86 g of the solution of Step E was added to a 500 mL round bottom flask and distilled to dryness, chased twice with acetonitrile and then was dissolved in acetonitrile (100 mL). To the solution was added 4-methylbenzenesulfonic acid hydrate (11.68 g) upon which a solid precipitated out and temperature rose to 40 C. The slurry was mixed at 50 C for 2 hours and cooled to 20 C for 12 hours. Solids were filtered and washed with 40 mL acetonitrile.
The wetcake was dried under vacuum to give 14.24 g of product (77% yield). 1H
NMR (400 MHz, Deuterium Oxide-d2) 6 2.79 (d, J = 7.0 Hz, 2H), 1.48-1.68 (m, 5H), 1.31-1.46 (m, 2H), 0.90-1.29 (m, 5H).
Example 12: Synthesis of 4-({[(1R,4R)-4-hydroxy-4-methyleyclohexyl]methyll-amino)-3-nitrobenzenesulfonamide (Compound (P)) [00166] 4-chloro-3-nitrobenzenesulfonamide (6.5 g, 27.5 mmol) and ((1R,4R)-4-hydroxy-4-methylcyclohexyl)methanaminium 4-methylbenzenesulfonate (11.26 g, 35.7 mmol) were combined in 35 mL of acetonitrile and stirred. N,N-diisopropylethylamine (8.88 g, 68.7 mmol) was added to the slurry at ambient temperature to result in an endotherm (200 to 17.5 C). After minutes, the reaction mixture was heated to 80 C and maintained at that temperature for 24 hours. The reaction was monitored for completion by HPLC. Upon completion of the reaction, the reaction mixture was cooled to 40 C. Water (32.5 mL) was added over 15 minutes and held for 30 minutes. An additional 74.5 mL of water was added over 30 minutes.
Solid product precipitated soon after the second portion of water was added. After stirring for 1 hour at 40 C,
[00164] Step E: RaNi (* d / (d-1) or * 7/6) = 2.04 g (20 wt%) was decanted 3 times with THF.
The RaNi, solution of (1R,4R)-1-methyl-4-(nitromethyl)cyclohexanol and THF (50 mL) were added under nitrogen in a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen, hydrogen and the hydrogenation was carried out at 40 psi for 4 hours at 50 C.
The reaction was monitored by GC and upon completion, it was filtered through a propylene filter funnel with diatomaceous earth/polyethylene fritted disc to remove catalyst. THF was used as a rinse to extract residual product from the filter cake. The combined filtrate gave an amber solution which was carried directly to next step. 1H NMR (400 MHz, Chloroform-di) 6 2.61 (d, J = 6.5 Hz, 2H), 1.25-1.50 (m, 12H), 0.80-1.17 (m, 3H).
[00165] Step F: 9.86 g of the solution of Step E was added to a 500 mL round bottom flask and distilled to dryness, chased twice with acetonitrile and then was dissolved in acetonitrile (100 mL). To the solution was added 4-methylbenzenesulfonic acid hydrate (11.68 g) upon which a solid precipitated out and temperature rose to 40 C. The slurry was mixed at 50 C for 2 hours and cooled to 20 C for 12 hours. Solids were filtered and washed with 40 mL acetonitrile.
The wetcake was dried under vacuum to give 14.24 g of product (77% yield). 1H
NMR (400 MHz, Deuterium Oxide-d2) 6 2.79 (d, J = 7.0 Hz, 2H), 1.48-1.68 (m, 5H), 1.31-1.46 (m, 2H), 0.90-1.29 (m, 5H).
Example 12: Synthesis of 4-({[(1R,4R)-4-hydroxy-4-methyleyclohexyl]methyll-amino)-3-nitrobenzenesulfonamide (Compound (P)) [00166] 4-chloro-3-nitrobenzenesulfonamide (6.5 g, 27.5 mmol) and ((1R,4R)-4-hydroxy-4-methylcyclohexyl)methanaminium 4-methylbenzenesulfonate (11.26 g, 35.7 mmol) were combined in 35 mL of acetonitrile and stirred. N,N-diisopropylethylamine (8.88 g, 68.7 mmol) was added to the slurry at ambient temperature to result in an endotherm (200 to 17.5 C). After minutes, the reaction mixture was heated to 80 C and maintained at that temperature for 24 hours. The reaction was monitored for completion by HPLC. Upon completion of the reaction, the reaction mixture was cooled to 40 C. Water (32.5 mL) was added over 15 minutes and held for 30 minutes. An additional 74.5 mL of water was added over 30 minutes.
Solid product precipitated soon after the second portion of water was added. After stirring for 1 hour at 40 C,
-42-the product mixture was allowed to cool to 20 C, stirred for 12 hours, and then cooled to 0 C
with stirring for 2 additional hours. The product was filtered and dried under vacuum to afford 8.8 g of product (Yield 93%; purity >99 pa%). 11-INMR (400 MHz, DMSO-d6) 6 ppm 8.52 (t, J
= 5.9 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 9.1, 2.3 Hz, 1H), 7.24-7.30 (m, 3H), 4.23 (s, 1H), 1.60-1.74 (m, 3H), 1.52-1.57 (m, 2H), 1.26-1.40 (m, 2H), 1.06-1.25 (m, 5H).
Example 13: Synthesis of 4-(4-1[2-(4-ehloropheny1)-4,4-dimethyleyelohex-1-en-l-yl[methyllpiperazin-1-y1)-N-(13-nitro-4-[(1R,4R)44-hydroxy-4-methylcyclohexyl[methyliamino]phenyllsulfony1)-2-(1H-pyrrolo12,3-b]pyridin-5-yloxy)benzamide (Compound (2)) [00167] The Sulfonamide 4-((((1R,4R)-4-hydroxy-4-methylcyclohexyl)methyDamino)-nitrobenzenesulfonamide (8.00 g, 23.29 mmol), EDAC-HC1 (5.80 g, 30.3 mmol) and DMAP
(8.54 g, 69.9 mmol) were mixed in DCM (186 mL, 14 vol) to a golden slurry. A
solution of acid, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(44(4'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-yl)methyl)piperazin-1-y1)benzoic acid (13.3 g, 23.29 mmol) and TEA (6.49 mL, 46.6 mmol) in DCM (80mL, 6 vol) was added over 2.5 hrs by addition funnel followed by a rinse with 10 mL DCM. After mixing for 12 hours, M,N/-dimethylethane-1,2-diamine (5.09 mL, 46.6 mmol) was added and stirring continued at 20 C for 5 hours. The reaction mixture was washed with 10% HOAc (130mL, 3x). The organic layer was washed with 5% NaHCO3 (140mL) and 5% NaC1(140mL). The organic layer was dried over Na2SO4. and concentrated to 7 volume of DCM solution. Methanol (10 vol, 140mL) was added dropwise over 2 hours, and the solution cooled to 15 C upon which the product precipitated. The product mixture was cooled to 5 C and mixed for 2 hours. Upon filtration of the solid and blow drying with nitrogen for 2 hours, 17.35 g of product was obtained (Yield 83%; purity >99.5 pa %).
1H NMR (400 MHz, DMSO-d6) 6 ppm 11.57-11.59 (bs, 1H), 8.48-8.52 (m, 2H), 7.97 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.2, 2.3 Hz, 1H), 7.43-7.50 (m, 3H), 7.29-7.31 (m, 2H), 6.98-7.03 (m, 3H), 6.65 (dd, J =
8.9, 2.3 Hz, 1H), 6.35 (dd, J = 3.4, 1.8 Hz, 1H), 6.16 (d, J= 2.2 Hz, 1H), 4.41-4.44 (m, 1H), 3.71-3.75 (m, 2H), 2.98-3.51 (m, 11H), 2.74-2.76 (m, 3H), 2.02-2.26 (m, 6H), 1.88-1.92 (m, 2H), 1.47-1.70 (m, 5H), 1.24-1.40 (m, 4H), 1.08 (s, 5H), 0.89 (s, 6H).
[00168] While the methods provided herein have been described with respect to the particular embodiments, it will
with stirring for 2 additional hours. The product was filtered and dried under vacuum to afford 8.8 g of product (Yield 93%; purity >99 pa%). 11-INMR (400 MHz, DMSO-d6) 6 ppm 8.52 (t, J
= 5.9 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 9.1, 2.3 Hz, 1H), 7.24-7.30 (m, 3H), 4.23 (s, 1H), 1.60-1.74 (m, 3H), 1.52-1.57 (m, 2H), 1.26-1.40 (m, 2H), 1.06-1.25 (m, 5H).
Example 13: Synthesis of 4-(4-1[2-(4-ehloropheny1)-4,4-dimethyleyelohex-1-en-l-yl[methyllpiperazin-1-y1)-N-(13-nitro-4-[(1R,4R)44-hydroxy-4-methylcyclohexyl[methyliamino]phenyllsulfony1)-2-(1H-pyrrolo12,3-b]pyridin-5-yloxy)benzamide (Compound (2)) [00167] The Sulfonamide 4-((((1R,4R)-4-hydroxy-4-methylcyclohexyl)methyDamino)-nitrobenzenesulfonamide (8.00 g, 23.29 mmol), EDAC-HC1 (5.80 g, 30.3 mmol) and DMAP
(8.54 g, 69.9 mmol) were mixed in DCM (186 mL, 14 vol) to a golden slurry. A
solution of acid, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(44(4'-chloro-5,5-dimethy1-3,4,5,6-tetrahydro-[1,1'-bipheny1]-2-yl)methyl)piperazin-1-y1)benzoic acid (13.3 g, 23.29 mmol) and TEA (6.49 mL, 46.6 mmol) in DCM (80mL, 6 vol) was added over 2.5 hrs by addition funnel followed by a rinse with 10 mL DCM. After mixing for 12 hours, M,N/-dimethylethane-1,2-diamine (5.09 mL, 46.6 mmol) was added and stirring continued at 20 C for 5 hours. The reaction mixture was washed with 10% HOAc (130mL, 3x). The organic layer was washed with 5% NaHCO3 (140mL) and 5% NaC1(140mL). The organic layer was dried over Na2SO4. and concentrated to 7 volume of DCM solution. Methanol (10 vol, 140mL) was added dropwise over 2 hours, and the solution cooled to 15 C upon which the product precipitated. The product mixture was cooled to 5 C and mixed for 2 hours. Upon filtration of the solid and blow drying with nitrogen for 2 hours, 17.35 g of product was obtained (Yield 83%; purity >99.5 pa %).
1H NMR (400 MHz, DMSO-d6) 6 ppm 11.57-11.59 (bs, 1H), 8.48-8.52 (m, 2H), 7.97 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.2, 2.3 Hz, 1H), 7.43-7.50 (m, 3H), 7.29-7.31 (m, 2H), 6.98-7.03 (m, 3H), 6.65 (dd, J =
8.9, 2.3 Hz, 1H), 6.35 (dd, J = 3.4, 1.8 Hz, 1H), 6.16 (d, J= 2.2 Hz, 1H), 4.41-4.44 (m, 1H), 3.71-3.75 (m, 2H), 2.98-3.51 (m, 11H), 2.74-2.76 (m, 3H), 2.02-2.26 (m, 6H), 1.88-1.92 (m, 2H), 1.47-1.70 (m, 5H), 1.24-1.40 (m, 4H), 1.08 (s, 5H), 0.89 (s, 6H).
[00168] While the methods provided herein have been described with respect to the particular embodiments, it will
-43-be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope as recited by the appended claims.
[00169] The embodiments described above are intended merely to be exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
[00169] The embodiments described above are intended merely to be exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
-44-
Claims (16)
1. A process for the preparation of a compound of formula (C):
wherein R is C1 to C12 alkyl, which comprises:
(a) combining a compound of formula (A):
with R1MgX in an aprotic organic solvent; wherein R1 is C1 to C6 alkyl and X
is Cl, Br or I;
(b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
wherein R is C1 to C12 alkyl, which comprises:
(a) combining a compound of formula (A):
with R1MgX in an aprotic organic solvent; wherein R1 is C1 to C6 alkyl and X
is Cl, Br or I;
(b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
2. The process of claim 1 wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.
3. The process of claim 1 or claim 2 wherein R1 is isopropyl.
4. The process of claim 1 or claim 2 wherein R is ethyl and the C1 to C12 alkyl chloroformate is ethyl chloroformate.
5. The process of claim 1 or claim 2 wherein R is methyl and the C1 to C12 alkyl chloroformate is methyl chloroformate.
6. The process of claim 1 or claim 2 wherein R is tert-butyl and the di-(C1 to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
7. A compound of the formula:
8. A process for the preparation of a compound of formula (D):
wherein the process comprises:
(x) combining a compound of formula (B):
with a compound of formula (C):
(C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
wherein the process comprises:
(x) combining a compound of formula (B):
with a compound of formula (C):
(C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
9. The process of claim 8, wherein the compound of formula (C) is prepared according to the following steps:
(a) combining a compound of formula (A):
with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
(a) combining a compound of formula (A):
with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
10. The process of claim 9, wherein the di-(C1 to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
11. A compound of the formula:
12. A process for the preparation of a compound of formula (3):
wherein the process comprises:
(y) combining a compound of formula (B):
with a compound of formula (C):
(C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D):
, wherein R is tert-butyl;
(z) combining the compound of formula (D), wherein R is tert-butyl;
with a compound of formula (I):
a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (3).
wherein the process comprises:
(y) combining a compound of formula (B):
with a compound of formula (C):
(C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D):
, wherein R is tert-butyl;
(z) combining the compound of formula (D), wherein R is tert-butyl;
with a compound of formula (I):
a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (3).
13. The process of claim 12, wherein the source of palladium is Pd2dba3.
14. The process of claim 13, wherein the phosphine ligand is a compound of formula (J):
15. The process of claim 14, wherein the compound of formula (C) is prepared according to the following steps:
(a) combining a compound of formula (A):
with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
(a) combining a compound of formula (A):
with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is Cl, Br or I; and (b) combining a C1 to C12 alkyl chloroformate or a di-(C1 to C12 alkyl)dicarbonate with the product of step (a), to provide the compound of formula (C).
16. The process of claim 15, wherein the di-(C1 to C12 alkyl)dicarbonate is di-tert-butyl dicarbonate.
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